Bone Science PDF

Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Bone cells Hello and welcome to the first lecture in our series on bone science, which will focus pretty much exclusiv...

Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Bone cells Hello and welcome to the first lecture in our series on bone science, which will focus pretty much exclusively on the 4 types of cell that form bone. In the next video, we’ll put these facts in a bit more context by looking at bone structure, but for now it’s useful for you to get to know the main players that are involved in all the various functions that we talked about in the roles of the skeleton video. The key points to take away, and hence the ones that are the most examinable, are the names of each cell, where they come from, what they do and what signalling pathways they’re involved in. 1  Body in Motion Bone cells MBChB Bone cells So let’s get started with a brief overview of each of the 4 main cell types that exist in bone, as shown here. Osteocytes, are cells that maintain the bone tissue, Osteoblasts, produce bone matrix Osteoclasts, resorb bone (meaning they remove existing bone) And osteogenic cells are precursor cells that differentiate into various different lines of cells depending on the mechanical environment they exist in. We’ll now look at each cell individually, defining their functions, features and how they interact with each other. 2  Body in Motion Osteoprogenitor cells MBChB Bone cells Mesenchymal stem cells Multiple possible fates Adipocytes Myocytes Chondrocytes Osteoblasts (via pre-OB) Locations Bone marrow Endo/periosteum Osteoprogenitor cells, also known as osteogenic cells, are mesenchymal stem cells, meaning they derive from the foetal mesenchyme, that are involved in both bone repair and growth. They are precursors to the more specialized bone cells and can differentiate into a number of different cells depending on their environment and chemical signalling. This includes adipocytes, myocytes, chondrocytes and osteoblasts. They can be present within the bone marrow, the endosteum and the cellular layer of the periosteum. OCPs fate determined by environment. When there is minimal movement (known as strain) in the local environment, they become osteoblasts. This is signalled by RunX2 and osterix, released by osteocytes that sense movement via mechanotransduction. If there is more movement in the local tissues, they become chondrocytes. This has clinical importance in fracture healing as if there is a lot of movement between fracture fragments, hard, bony callus may never form and a non-union occurs. This can be prevented with adequate immobilisation of a fracture, for example with a plaster cast or a metal plate and screws. 3  Body in Motion Osteoblasts MBChB Bone cells Origin Osteoprogenitor cells Runx2 and osterix Location Peri/endosteum Bone surfaces (‘inactive’) Osteoblasts are cells with a single nucleus and derive from undifferenctiated mesenchymal stem cells. The OPC differentiate into Pre‐OB to OB under the influence of signalling factors Runx2 and osterix, as mentioned previously. 4  Body in Motion MBChB Osteoblasts Bone cells Functions Bone production PTH Type 1 collagen ALP Vit D Matrix proteins ALP Pre‐OB to OB controlled by signalling factors Runx2 and osterix, as mentioned previously. Osteoblasts have 2 main functions, the first of which is to form bone by producing non‐mineralised matrix. To aid in this, they have increased amounts of endoplasmic reticulum, golgi apparatuses and mitochondria than other cells, allowing them to synthesise and secrete the bone matrix. When stimulated by PTH, they produce type 1 collagen and alkaline phosphatase, which is an enzyme that dephosphorylates many organic molecules, initiating the calcification of the matrix by laying down deposits of calcium phosphate. They also have a vit D receptor and when stimulated, OBs produce matrix, ALP and specific bone proteins like osteocalcin and osteonectin. 5  Body in Motion Osteoblasts MBChB Bone cells Functions Bone production Osteoclast regulation RANK-L Stimulates bone resorption Osteoprotegrin (OPG) Inhibits bone resorption Their second function is in regulating osteoclast function via the RANK/OPG axis. In response to PTH, osteoblasts release RANK‐Ligand which is a signalling molecule that binds to the corresponding receptor, called RANK, and stimulates osteoclast precursors to become active osteoclasts, thus stimulating bone resorption. They also secrete osteoprotegrin, which is a decoy receptor that irreversibly binds to free RANK ligand, preventing it from attaching to RANK on the osteoclast precursors. OPG therefore inhibits the differentiation, fusion and activation of osteoclasts and therefore inhibits prevents bone resorption. 6  Body in Motion Osteoblasts MBChB Bone cells Fate Life span 6 months Osteocytes Apoptosis Lining cells The average life span of an osteoblast is around 6 months, after which it can have one of 3 fates. About 10‐15% of osteoblast become entombed in the matrix they have produced and become osteocytes, which we’ll talk about in a moment. The rest either die by apoptosis or differentiate into lining cells, that sit on the surface of quiescent bone. These lining cells are flattened, inactive osteoblasts that have the potential to become mature osteoblasts for future remodelling. 7  Body in Motion MBChB Osteocytes Bone cells Former OBs trapped in matrix Function Maintain bone Regulate Ca/PO Features Long cellular processes Signalling Calcitonin PTH Osteocytes are former Obs that become trappe in the matrix that they have produced and account for around 90% of the cells in the mature skeleton. They have long cellular processes which are used to communicate with neighbouring cells through small channels in the bone called canaliculi. You can see the network of canaliculi in the image on the right, as part of the cortical haversian system. Osteocytes maintain the bone and cellular matrix, regulating the concentrations of calcium and phosphorus in bone. When tissue is placed under compressive load, fluid is squeezed out of the area under load and flows to an area of lower compression. The osteocytes are able to sense this movement of fluid and this process is know as mechanotransduction. They are then able to signal over long distances via the cellular processes, much like in the nervous system. 8  Body in Motion MBChB Osteocytes Bone cells Former OBs trapped in matrix Function Maintain bone Regulate Ca/PO Features Long cellular processes Signalling Calcitonin PTH Regulation of bone remodelling is in response to this local mechanical or systemic e.g. parathyroid hormone (PTH) signals. They increase osteoclast formation by increased expression of RANKL, similar to OBS, leading bone resorption inhibits osteoblast formation by production of Sclerostin = decreased bone formation. Sclerostin production inhibited by PTH and mechanical loading = increased bone formation Responds to increasing PTH levels by inducing rapid calcium release (osteocytic osteolysis) 9  Body in Motion Osteoclasts MBChB Bone cells Multinucleated giant cells Monocyte/macrophage lineage Function Resorb bone Hydroxyapatite Inorganic matrix Features Ruffled border Signalling RANK/OPG axis (OBs) Calcitonin inhibits Osteoclasts are multinucleated giant cells, formed from the fusion of multiple myeloid haematopoietic cells from the monocyte/macrophage lineage. Their function is to reabsorb bone by first dissolving the inorganic hydroxyapatite and then the organic matrix by proteolytic digestion. They have receptors on their surface for calcitonin, which inhibits their activity and are activated by RANK‐Ligand, as already discussed. Once activated via the binding of RANK ligand, osteoclast progenitor cells fuse together to become multinucleate cells that migrate to the site of bone resorption and attach to the bone surface and become active osteoclasts. 10  Body in Motion Osteoclasts MBChB Bone cells Multinucleated giant cells Monocyte/macrophage lineage Function Resorb bone Hydroxyapatite Inorganic matrix Features Ruffled border Signalling RANK/OPG axis (OBs) Calcitonin inhibits As active osteoclasts, they seal one side of the cell to the bone surface at sealing zones and the cell polarises to have different membrane domains. At the top of this diagram, the surface away from the bone becomes the secretory domain, where products of degradation are released into the interstitial fluid. At the bone surface, the cell forms a ruffled border which vastly increases the surface area of the cell to aid secretion and absorption of enzymes and products of degradation. The cell then releases various substances including tartrate resistant acid phosphate, know as TRAP, which helps dissolve the inorganic hydroxyappetite, and proteolytic enzumes like cathepsin K, which break down the organic components. Resorption of bone forms a small pit, known as Howship’s lacunae. The ruffled border then resorbs the organic and inorganic products of degradation from the, HL, transporting them across the cell for excretion via the secretory domain. 11  Body in Motion Calcium homeostasis MBChB Bone cells All of this information is vital to understanding the homeostatic control of calcium, which we will begin to explore in later videos about metabolic bone disease. 12  Body in Motion Summary MBChB Bone cells Osteocytes maintain the bone tissue, Osteoblasts produce bone matrix Osteoclasts resorb bone Osteogenic cells are precursors of a variety of cell lines So here we are back at the quick overview of the different cells, starting with osteocytes, which maintain the bone tissue, osteoblasts which produce bone matrix, osteoclasts which resorb bone and the precursos osteogenic cells that differentiate into a variety of cell lines. 13  Body in Motion Closing task MBChB Bone cells Fill in the table, which summarises the key features of each bone cell Osteoprogenitors Osteoblasts Osteocytes Osteoclasts Origin Location Features Function Signalling Other notes Your closing task for this video is to fill in the table that summarises the features of each type of cell, which should give you a handy reference for revision and future lectures. As usual, see how much you can fill in from memory before you check over your work and fill in the gaps. 14 Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Bone remodelling 1  Body in Motion MBChB Content Bone remodelling Bone remodelling Bone mineralisation 2  Body in Motion MBChB Bone remodelling Bone remodelling Removal of small increments of bone and replacement with new Structural Removal of micro-damaged bone Bone remodelling is the cycle by which small increments of bone are removed and then replaced by new bone. It’s a process that goes on continuously throughout our life at varying rates of activity. So we could ask, why do our bones need to remodel? Surely, like a building we can construct the structural framework as we’re built and then it will do it’s job without much maintenance? Well you probably know that buildings aren’t just constructed and then left alone, and in fact do undergo constant maintenance and repair, just like the human skeleton. One of the more recent developments in materials science is so called self-healing or bio-cement that can repair small cracks, even deep in the material, without any external input. This is something the skeleton does just fine on its own and is one of the main reasons for remodelling. 3  Body in Motion MBChB Bone remodelling Bone remodelling Removal of small increments of bone and replacement with new Structural Removal of micro-damaged bone Healing macro-damaged bone As a person goes about their daily life, their bones experience a great number of tiny traumas to them, resulting in areas of micro-damage or micro-fracture. If these very limited areas of damage aren’t repaired, then they weaken the bone and lead to further damage around them, eventually resulting in mechanical failure, ie fracture. We’ll see a clinical example of this when we talk about one of the side effects of bisphosphonate treatment. In addition to micro-damage, remodelling is needed to repair macro-damaged bone, ie in fractue healing. 4  Body in Motion MBChB Bone remodelling Bone remodelling Removal of small increments of bone and replacement with new Structural Removal of micro-damaged bone Healing macro-damaged bone Response to changing loads We’ve also seen that, unlike a building which stays in one place under fairly constant conditions, bones need to respond to changing loads and forces put across them. They can achieve this response through remodelling, resorbing bone where it’s not needed and reinforcing where the load is greatest, which is according to Wolfe’s law. 5  Body in Motion MBChB Bone remodelling Bone remodelling Removal of small increments of bone and replacement with new Structural Removal of micro-damaged bone Healing macro-damaged bone Response to changing loads Metabolic Storage and release of calcium Finally, as we all know, an important role of the skeleton is as a warehouse to store and release calcium, as part of calcium homeostasis. 6  Body in Motion MBChB Bone remodelling Bone remodelling Occurs throughout life 5 – 15% of bone surface normally remodelling in adults 18 % of skeleton replaced each year in adults cancellous bone 20% cortical bone 2% The process of bone remodelling occurs throughout a person’s life and at any one moment about 5-15% of the surface of adult bones are undergoing remodelling. Over the course of a year, about 18% of an adult skeleton is replaced with new bone, meaning over a course of a person’s life, the fabric of their skeleton will have been replaced several times over. This brings up the philosophical concept of the ship of Theseus. For anyone who hasn’t heard of this thought experiment, ancient Greek philosophers pondered whether years of replacing broken planks of wood in the hero Thesues’s ship would reach a point where no original wood was left on the ship, and was it therefore even the same vessel as when it left it’s shipyard in old Athen’s? That tangent won’t be tested in any of your exams but it’s one of the oldest thought experiments in western philosophy so worth a read on wikipaedia. 7  Body in Motion MBChB Bone remodelling Bone remodelling Occurs throughout life 5 – 15% of bone surface normally remodelling in adults 18 % of skeleton replaced each year in adults cancellous bone 20% cortical bone 2% This remodelling happens primarily in cancellous bone, as the stress is more variable here than in cortical bone, with around 20% of cancellous bone remodelling in a year compared to 2% of cortical. 8  Body in Motion MBChB Bone remodelling cycle Bone remodelling Quiescence Resorption Reversal Formation Remodelling is a cyclical process, which constantly resorbs and deposits bone in response to local or systemic triggers. It’s sometimes described as going through 4 stages, of quiescence, resorption, reversal and formation, although I think it’s possibly easier to think of it as a 5 or 6 step process, which adds in activation and mineralisation as separate steps. We’ll go through these stages individually now. 9  Body in Motion MBChB Bone remodelling cycle Bone remodelling Quiescence Resting state 90% of bone Osteoblasts Inactive Line the bone surface Osteocytes Maintain matrix Sense changes in mechanical environment Inhibit OB activity (sclerostin) The term quiescence can be defined as a state or period of inactivity or dormance, and refers to the resting state of bone, when it is not actively being remodeled. About 90% of bone is in this state, while the other 10% is in turnover. Osteoblasts in quiescent bone are inactive, flattened cells that line the surface of the bone and pass the time waiting for an activation signal. Osteocytes maintain the bone matrix and monitor for mechanical changes in the local environment. They also produce a protein called sclerostin, which inhibits osteoblastic activity and keeps the bone in its resting state. 10  Body in Motion MBChB Bone remodelling cycle Bone remodelling Activation Systemic Activation PTH, Vit D Endocrine hormones Local Mechanical stress Microdamage RANK-L and M-CSF release Recruit, differentiate and activate OCs To progress from quiescence to the next stage, something needs to happen to tell the osteoblasts to get the process going, which can be either a local or a systemic signal. Osteocytes in the local bone detect increased stress or microdamage and signal osteoblasts to release RANK-ligand and macrophage colony stimulating factor, which together begin the recruitment, differentiation and activation of osteoclasts. Systemic activation is by PTH and vit D, as well as some endocrine hormones like thyroid and growth hormones. Antagonistic to this are oestrogen and calcitonin which inhibit bone resorption and stimulate deposition. 11  Activation Body in Motion MBChB Bone remodelling Bone remodelling cycle Resorption Activated osteoclasts migrate Attach to bone Polarise Dissolve inorganic Dissolve organic Remove degradation products J Dent Res. 2013 Oct; 92(10): 860–867 Once the osteoclasts are activated by RANK ligand or MCSF, they migrate to the target site and begin the process of resorption, as described in the bone cells video. To remind you of the steps: The osteoclasts first attach Themselves to the bone with an watertight seal around the edge and then polarised themselves forming a ruffled border near the bone and a functional secretory domain on the side away from the bone. They then begin to release hydrochloric acid from their ruffled border which dissolves the inorganic bone material coma ie hydroxyapatite, and begin forming the how ships lacuna , sometimes called the resort ption pit. They then release protease is to dissolve the organic matrix before transporting all of the degradation products across the cell to be secreted through the fsd. Here we can see a microscope slide of the large multinucleated osteo clasts nibbling away at the bone matrix lamellar bone which we can see in orangey yellow with some osteo sites trapped in it. 12  Body in Motion MBChB Bone remodelling cycle Bone remodelling Reversal Osteoprogenitor cells Migrate to resorption pit Differentiate and activate Osteoclasts Apoptose or deactivate Signal to OPCs/OBs Once the osteoclast have resourcd the bone and created a pit they go onto apoptose or regrese to their deactivated form. While they are doing this they aid in signalling to the inactive osteoblasts to begin their own differentiation back into there active form and begin laying down new bone. There are various ways that the osteoblasts are activated in this way including direct osteoclast to osteoblast and through the release of signalling molecules from the resort bone. “It has recently been discovered that many of the drugs that are used clinically to inhibit bone resorption, such as bisphosphonates and oestrogen, do so by promoting osteoclast apoptosis.” 13  Body in Motion MBChB Bone remodelling cycle Bone remodelling Formation Osteoblasts New bone Lay down organic osteoid Type 1 collagen Osteocalcin Proteoglycans, etc Fill in pit Control mineralisation of osteoid Osteopontin Fate = osteocytes or bone lining Once these osteoblasts are activated they begin to form new bone by laying down knew organic osteoid. As we've seen already osteoid is made of type one collagen with various bone proteins like osteocalcin The osteoblasts fill in the resort Shen pit with this organic osteoid which then goes on to mineralise in a staged process so in this picture the new osteoid is in the yellow at the top whilst there's mineralisation going on of the new bone below this. The osteoblasts have a role in controlling the mineralisation of this osteoid as we'll find out in a moment and their final fate will either be to go back to become quiescent bone lining cells or two become trapped in the matrix and further differentiate into osteocytes. 14  Body in Motion MBChB Bone remodelling cycle Bone remodelling Mineralisation 75% happens in 1-2 weeks Then much slower Deposition of Hydroxyapatite Inorganic mineral of bone New bone Precipitate of soluble calcium and inorganic phosphate Soft osteoid into hard bone It's therefore useful to look at mineralisation as a separate step that happens concurrently with gnu osteoid being produced. Around 75% of mineralisation happens within the 1st week or two and then slows down to complete mineralization over many more weeks to months. Mineralisation itself is the deposition of hydroxyapatite crystals, which is the main inorganic mineral of bone and is a precipitate of soluble calcium and inorganic phosphate. This deposition of hydroxyapatite turns the soft unmineralised osteoid into hard mineralised bone 15  Body in Motion MBChB Bone remodelling cycle Bone remodelling Mineralisation 75% happens in 1-2 weeks Then much slower Deposition of Hydroxyapatite Inorganic mineral of bone Precipitate of soluble calcium and inorganic phosphate Soft osteoid into hard bone the actual process of mineralisation is poorly understood with a number of different theories as to how it happens. Most theory seemed to centre around the generation of matrix vesicles which are small sita plasmic buds that accumulate calcium and phosphate. These are released from the surface of osteoblasts and travel to the collagen fibrils Where the rupture and deposit their contents deposit their contents 2 begin formation of crystalline hydroxyapatite. 16  Body in Motion Regulation of Bone Mineralisation MBChB Bone remodelling Locally Systemically Predominantly by inorganic pyrophosphate Endocrine regulators of blood Ca2+ and PO4 Inorganic pyrophosphate = PPi Predominantly PTH Blocks calcification, inhibits Vitamin D hydroxyapatite formation FGF23 Present in ECF, synovial fluid, urine and Produced by osteocytes and blood plasma osteoblasts in response to increased Osteoblast-derived proteins active Vit D Osteocalcin - promotes mineralization Increases PPi secretion Osteopontin - Inhibits mineral Decreases PTH and Vitamin D levels binding/crystal growth the actual regulation of bone mineralization is achieved by both local and systemic mechanisms. Locally the presence of inorganic pyrophosphate act as a inhibitor two mineralisation. When in organic pyrophosphate which is sometimes abbreviated to PPI coma not to be confused with indigestion remedies or unwanted phone calls coma blocks calcification and inhibits hydroxyapatite formation. It's therefore present in fluids that contain calcium and phosphate but mineralisation would be problematic. This includes extracellular fluid synovial fluid urine and blood plasma. Feedback loop 17  Body in Motion Regulation of Bone Mineralisation MBChB Bone remodelling Locally Systemically Predominantly by inorganic pyrophosphate Endocrine regulators of blood Ca2+ and PO4 Inorganic pyrophosphate = PPi Predominantly PTH Blocks calcification, inhibits Vitamin D hydroxyapatite formation FGF23 Present in ECF, synovial fluid, urine and Produced by osteocytes and blood plasma osteoblasts in response to increased Osteoblast-derived proteins active Vit D Osteocalcin - promotes mineralization Increases PPi secretion Osteopontin - Inhibits mineral Decreases PTH and Vitamin D levels binding/crystal growth Other substances involved in local control include some proteins produced by osteoblasts like osteocalcin which promotes mineralisation and osteopontin which inhibits mineral binding and crystal growth. Systemic regulation involves many of the endocrine regulators of blood calcium and phosphate including predominantly parathyroid hormone and vitamin D. A recent discovery is the role that fibroblast growth factor 23 please by increasing inorganic pyrophosphate secretion and decreasing levels of parathyroid hormone and vitamin D. It's produced by osteocytes and osteoblasts in response to increased circulating active vitamin D so forms part of a negative feedback loop for vitamin D 18  Body in Motion MBChB Systemic regulation Bone remodelling Major hormonal regulators of osteoclastic bone resorption Increase PTH (via RANKL) Decrease Calcitonin (direct) and oestrogen (via RANKL) Major hormonal regulators of osteoblastic bone formation Increase PTH, vitamin D, oestrogen, growth hormone Just to remind you about systemic regulation of calcium and phosphate the major hormonal regulators of osteoclastic bone resorb shun include parathyroid hormone which increases it via rank ligand release from osteoblasts. Inhibitors of osteoclastic bone resumption include calcitonin which inhibits it directly and oestrogen by reducing rank ligand's expression. For osteoblastic bone formation the harmony regulators that increase it are parathyroid hormone vitamin D oestrogen and growth hormone. 19  Body in Motion MBChB Bone remodelling cycle Bone remodelling Quiescence Resorption Reversal Formation So that brings us back to the quiescent state of bone once the new bone has been mineralised and therefore closing the remodelling cycle. 20  Body in Motion MBChB Content Bone remodelling Bone remodelling Quiescence Resorption Reversal Formation Bone mineralisation Hydroxyapatite deposition Local and systemic control Abnormalities of bone remodelling and mineralisation give rise to ‘Metabolic Bone Diseases’ So to summarise this video we've looked at the stages of bone remodelling which include quiescence activation resorption reversal formation and mineralisation. mineralisation itself is the process of hydroxyapatite deposition in osteoid converting it from soft to hard bone and has local and systemic mechanisms for control. Abnormalities of any of the process as we've discussed in this video can give rise to the metabolic bone diseases which we'll discuss in more detail in a separate video. 21  Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Bone structure Hello and welcome to this lecture on the topic of bone structure, in which we’ll think about the various ways bone is organised in the human body, how we can classify the different types of bone and why any of this is useful to us as clinicians. 1  Body in Motion What is bone? MBChB Bone structure A rigid organ Multifunction Vertebrate ‘endoskeleton’ It’s sometimes useful to start thinking about a topic with a definition, so let’s ask ourselves: What is bone? In the most simple terms, bone is a rigid organ with a variety of functions including structural, endocrine and metabolic, to name a few. We’ve already discussed these functions in some detail in the Roles of the Skeleton video, so won’t go into them further here. A bony skeleton with a spinal collumn is a feature of all vertebrate animals and to be precise, an endo skeleton, as it exists inside the organism. This is in contrast to the exoskeletons of some invertebrates, that have their skeleton on the outside, such as crustacians and insects. 2  Body in Motion What is bone? MBChB Bone structure A rigid organ Multifunction Vertebrate ‘endoskeleton’ Bone tissue Dense connective tissue High compressive strength Low tensile and shear strength Rigid but significant elasticity Bone can further be defined as dense connective tissue with a high compressive strength, meaning it is strong when being pushed together, but low tensile strength, ie when it is being pulled apart. This difference in strength is dependant on how a load is applied which means it is therefore an anisotropic material. A final important property of adult bone is that it is relatively rigid, meaning it has resistance to bending forces, and exhibits significant elasticity, which means that it returns to its original shape after a deforming force is applied to it. This is in contrast to a plastic material, which changes shape permanently following application of a similar deforming force. You may note that I used the phrase ‘adult bone’ here, because, as we will find out in later videos, children’s bones have slightly different properties and can, in fact, undergo quite a bit of plastic deformity that wouldn’t happen in a mature bone. 3  Body in Motion MBChB The skeleton Bone structure Axial skeleton Bones of the head Spine Thorax So now that we've defined what bone is, let’s look a bit more at what makes up our skeletons. The human skeleton exists in two different parts, the axial skeleton and the appendicular skeleton. The axial skeleton consists of the bones of the head, including the inner ear, the rib cage and the vertebral column. It takes its name from the fact that it's located closest to the central axis of the human body 4  Body in Motion MBChB The skeleton Bone structure Axial skeleton Bones of the head Spine Thorax Appendicular skeleton Shoulder girdle Upper limb Pelvis Lower limb The appendicular skeleton is named for the bones that support the ‘appendages’, which is a term applied in both vertebrate and invertebrate biology, meaning an external body part that protrudes from an organisms body. We primarily use the term appendages to refer to the limbs but it can also include the sexual organs as well. The shoulder girdle is made up of the scapulae and the clavicles which then attach to the upper limb composed of the humerus, radius and ulna and the many bones of the hand. Although we often refer to the pelvis as the whole ring structure of the pelvic bones and sacrum, the appendicular pelvis is only composed of the 2 innominate bones, themselves formed by the fusion of the illium, ischium and pubis. Finally, the bones of the lower limb are the femur, tibia, fibula and the 26 bones in each foot. 5  Body in Motion MBChB Classification - Anatomical Bone structure Flat Short Sesamoid Irregular Long Now that we’ve looked at the gross organisation of the skeleton, we can look at how bones are classified. This can be anatomical or structural. Bones vary in size significantly, from the largest bone in the body, the femur, at an average 48cm to the stapes, one of the bones of the middle ear at 3mm. Flat bones are thin, flat or curved bones that sandwich a thin layer of cancellous bone between 2 layers of cortex. Examples are the majoiry of the bones of the skull and the sternum Short bones are usually roughly cube‐shaped, although that can be a bit of a stretch when you actually look at them individually. Examples are the carpal and tarsal bones of the wrist and foot respectively Sesamoid bones exist in the substance of tendons and act to improve the power the attached muscle by holding the tendon further from the center of the joint, thereby increasing its leverage. Examples include the patella in the knee and the pair of sesamoids under the great toe meta‐tarsophalangeal joint. Irregular bones don’t really fit into any category and have unique shapes that serve an individual purpose, such as the complex shape of spinal vertebrae that protect the spinal cord. 6  Body in Motion MBChB Classification - Anatomical Bone structure Cancellous Long bones bone Epiphysis Articular surface Cortical Contains physis/physeal scar bone Metaphysis Diaphysis Periosteum Blood supply Circumferential bone growth Fracture healing Long bones are defined by a few shared anatomical features. They all have three anatomic regions, which are the epiphysis, the metaphysis and the diaphysis. The epiphysis is the end of the bone that forms the articular surface, is covered in the articular cartilage and it contains the physis and subchondral region under the articular cartilage. It gets its name from EPI, meaning next to, so it's the part next to the physis. The metastasis gets its name from META, meaning changing, so it's the part that changes shape from the diaphysis to the epiphysis, and it's made of thin cortical bone surrounding a centre of loose trabecular bone. 7 The diaphysis gets its name from DIA, meaning between, between the two physes at the end of the bones, and it's made of thick cortical bone surrounding a central canal of bone marrow. 7  Body in Motion MBChB Classification - Anatomical Bone structure Cancellous Long bones bone Epiphysis Articular surface Cortical Contains physis/physeal scar bone Metaphysis Diaphysis Periosteum Blood supply Circumferential bone growth Fracture healing The outer region of the diaphysis is covered by periosteum, which is dense, irregular connective tissue and has a couple of functions. The first is to provide a blood supply to the bone, and the second to provide fibroblasts and progenitor cells that can develop into osteoblasts and chondroblasts. There's also an endosteum on the inside of the medullary cavity, which is primarily involved in bone turnover and remodelling. The cells in the periosteum are also important in fracture healing as they provide these progenitor cells for bone healing. It’s fairly obvious that the bones of the leg and arm are long bones, that is the humerus, radius, ulna, femur, tibia and fibula, but any bone that has this structure of 8 epiphysis, metaphysis, diaphysis is considered a long bone. So, many bones in the hand and foot are long bones, despite not being particularly long. This includes the metacarpals, the metatarsals and all of the phalanges in the fingers and toes. 8  Body in Motion MBChB The physis Bone structure Specialised zone of cartilage Site of longitudinal growth Fusion at /after puberty Long bone growth stops 16 males 14 females Medial clavicle physis at 23-25 We’ve mentioned the physis already and we’ll look at it in more detail in another video, but for now you should know that the physis, otherwise known as the growth plate, is a specialised zone of cartilage located at the ends of long bones that is responsible for longitudinal growth. Because it’s made of cartilage, and hence is much less dense than the surrounding bone, it appears on a radiograph as a line of lucency near the articular surface. On this top radiograph, you can see the physes of the distal femur, proximal tibia and proximal fibula, highlighted by the red arrows. As a child becomes an adult and stops growing, their 9 physes fuse and the lucent lines on a radiograph therefore disappear but can sometimes be seen as a sclerotic, ie denser, line on radiographs, as seen in the lower image here, highlighted by the blue arrow. 9  Body in Motion MBChB Classification - Structural Bone structure Macroscopic Cortical Cancellous Microscopic Woven Lamellar We’ve looked at anatomical classification, but we can also classify bones but how they are structured, both macroscopically and microscopically. The image on the right shows a section of the proximal femur, demonstrating cortical bone in the diaphysis and cancellous, sometimes called trabecular or spongy bone, in the epiphysis. 10  Body in Motion Macroscopic organisation MBChB Bone structure Proportion of cortical / cancellous bone varies in different parts and types of the bone Mid bone / diaphysis – most cortical little cancellous bone End of bone / epiphysis – predominantly cancellous bone The proportions of these 2 different types of bone vary depending on their location. In the diaphysis of a long bone there is almost no cancellous bone at all as the thick cortices make up the majority here. You can see this on the radiograph on the right, where the cortices become thicker as you approach the midpoint of the diaphysis. The point where the cortices are thickest, and therefore the medullary canal is narrowest, is known as the isthmus. At the end of the bone, in the metaphysis and epiphysis the proportion changes to become predominantly cancellous bone, surrounded by a thin layer of cortex and covered by articular cartilage at the joint surface. 11  Body in Motion MBChB Macroscopic organisation Bone structure Proportion of cortical / cancellous bone varies in different parts and types of the bone Mid bone / diaphysis – most cortical little cancellous bone End of bone / epiphysis – predominantly cancellous bone So why do these proportions change? Well it’s all related to the different mechanical requirements in the different parts of the bone. The diaphysis of a bone acts as a lever, allowing muscles to move the joint with increased power. Think of it a bit like a crowbar, with a long lever arm and a fulcrum, or centre of rotation, at the joint. When a force is applied at a distance to the fulcrum, the force is multiplied depending on how far this distance is, so a longer lever means a greater force at the fulcrum for the same force applied to the lever. This also means that the lever itself, ie the bone, needs to be very strong and rigid to transfer the muscle force to the joint without breaking. Thick cortices, getting thicker the further they are from the joint therefor keep the diaphysis strong and rigid to resist these bending forces. 12  Body in Motion MBChB Macroscopic organisation Bone structure Proportion of cortical / cancellous bone varies in different parts and types of the bone Mid bone / diaphysis – most cortical little cancellous bone End of bone / epiphysis – predominantly cancellous bone So why do these proportions change? Well it’s all related to the different mechanical requirements in the different parts of the bone. The diaphysis of a bone acts as a lever, allowing muscles to move the joint with increased power. Think of it a bit like a crowbar, with a long lever arm and a fulcrum, or centre of rotation, at the joint. When a force is applied at a distance to the fulcrum, the force is multiplied depending on how far this distance is, so a longer lever means a greater force at the fulcrum for the same force applied to the lever. This also means that the lever itself, ie the bone, needs to be very strong and rigid to transfer the muscle force to the joint without breaking. Thick cortices, getting thicker the further they are from the joint therefor keep the diaphysis strong and rigid to resist these bending forces. 13  Body in Motion MBChB Macroscopic organisation Bone structure Proportion of cortical / cancellous bone varies in different parts and types of the bone Mid bone / diaphysis – most cortical little cancellous bone End of bone / epiphysis – predominantly cancellous bone So why do these proportions change? Well it’s all related to the different mechanical requirements in the different parts of the bone. The diaphysis of a bone acts as a lever, allowing muscles to move the joint with increased power. Think of it a bit like a crowbar, with a long lever arm and a fulcrum, or centre of rotation, at the joint. When a force is applied at a distance to the fulcrum, the force is multiplied depending on how far this distance is, so a longer lever means a greater force at the fulcrum for the same force applied to the lever. This also means that the lever itself, ie the bone, needs to be very strong and rigid to transfer the muscle force to the joint without breaking. Thick cortices, getting thicker the further they are from the joint therefor keep the diaphysis strong and rigid to resist these bending forces. 14  Body in Motion Macroscopic organisation MBChB Bone structure Proportion of cortical / cancellous bone varies in different parts and types of the bone Mid bone / diaphysis – most cortical little cancellous bone End of bone / epiphysis – predominantly cancellous bone As we get closer to the joint surface into the metaphysis and epiphysis, the bending forces reduce so there isn’t such a need to have thick cortices to withstand them. The main forces experienced by the bone here are compressive forces and particulary the sudden shock forces as weight is suddenly applied to the joint, when the foot hits the ground during walking or running. The spongy trabecular bone here is therefore organised to support the articular surface, resist impact and transfer weight evenly through the bone. 15  Body in Motion Macroscopic - Cortical MBChB Bone structure 80% of skeleton Slow turn-over rate High rigidity Resists bending/torsion Thicker in mid-diaphysis Haversian systems Osteons Vascular canals Interstitial lamellae Let’s zoom in a bit for a closer look, although we’ll still call this macroscopic structure, and think about how cortical bone is organised. Cortical bone, which makes up around 80% of the skeleton, has a high rigidity to resist the bending and torsional forces required of a lever, as we found out earlier. It has a slow turn‐over rate, ie the cycle of formation and re‐sorption happens very gradually. 16  Body in Motion Macroscopic - Cortical MBChB Bone structure 80% of skeleton Slow turn-over rate High rigidity Resists bending/torsion Thicker in mid-diaphysis Haversian systems Osteons Vascular canals Interstitial lamellae The main structural unit of cortical bone is called an osteon, which you can see labelled in the diagram on the right. Osteons are bone cylinders around 2‐3 millimetres long that have between 8‐15 concentric rings of bone, known as lamellae, each around 0.2 millimetres wide. They have their axis parallel to the long axis of the bone and have channels that contains neurovascular structures, known as Haversian canals if parallel to the axis of the bone, or Volksman’s canals, labelled as perforating canals on this image, if perpendicular to the axis. Together, these form a neurovascular network throughout the bone with connections between the 17 individual osteons. 17  Body in Motion Macroscopic - Cortical MBChB Bone structure 80% of skeleton Slow turn-over rate High rigidity Resists bending/torsion Thicker in mid-diaphysis Haversian systems Osteons Vascular canals Interstitial lamellae Here we can see a light microscopy slide of a bone sample. On it, we can see a transverse section through a cortical bone, so we're looking down at the top of an osteon. In the middle, we can see the Haversian canal and then we can see the concentric rings of lamellae going out from there. This red line shows the outer limit of an osteon and we can also see a transverse canal, so one of the Volksman’s canals, in blue in the top right of the image, which we've taken a section through. 18  Body in Motion Macroscopic - Cortical MBChB Bone structure 80% of skeleton Slow turn-over rate High rigidity Resists bending/torsion Thicker in mid-diaphysis Haversian systems Osteons Vascular canals Interstitial lamellae Here we can see a light microscopy slide of a bone sample. On it, we can see a transverse section through a cortical bone, so we're looking down at the top of an osteon. In the middle, we can see the Haversian canal and then we can see the concentric rings of lamellae going out from there. This red line shows the outer limit of an osteon and we can also see a transverse canal, so one of the Volksman’s canals, in blue in the top right of the image, which we've taken a section through. 19  Body in Motion Macroscopic - Cancellous MBChB Bone structure Loose network of struts Less rigid, more elastic Struts approx. 200 microns High surface area for metabolic Fx High turnover Remodels according to stress Wolff’s law Mechanotransduction We’ll now move on to thinking about the structure of cancellous bone. Cancellous bone is organised as a loose network of struts, making it less rigid and more elastic than cortical bone. Each of these structs is around 200 microns in diameter, and this organisation gives it a very high surface area for metabolic functions. This means it's important for calcium homeostasis so turnover in cancellous bone is very high when compared to cortical bone. This not only contributes to calcium homeostasis, but also means that the bone can remodel quickly according to stress, which can be described using Wolff's Law, which states that bone will adapt to the load under 20 which it's placed. So bones under increased load will remodel to become stronger over time, importantly, only in response to the particular type of loading it undergoes. When bone is loaded, for example with normal weight‐ bearing, fluid is forced away from areas of the bone matrix that are under high compression, a bit like squeezing a sponge, albeit a very hard one. Osteocytes encased in the bone can sense this movement of fluid and stimulate the remodelling cycle either via direct contact, using their long cellular processes, or by signalling pathways such as the rank OPG axis. Examples of bone being remodelled to strengthen it can be seen in weightlifters, who often have higher bone density, and interestingly, in tennis players, but only in their racket arm, which experiences very high load during that serve. Of course, the inverse of this is true as well, so if load decreases or is removed, then bone will be resorbed and hence become weaker. Clinical examples of this decreasing strength and density can be seen in patients with prolonged immobility or in astronauts who spend long periods of time in microgravity. 20  Body in Motion MBChB Macroscopic - Cancellous Bone structure ‘Trabecular’ bone Strength without weight Organised along lines of maximum mechanical stress Allows transmission of loads Support areas of maximum stress Strut connections increase strength Cancellous bone is sometimes called trabecular bone, due to the trabeculae that are organised along lines of maximum mechanical stress. This structure of the bone gives a great deal of strength, without the weight of a solid bone, and can be thought of as a bit like the struts of a bridge, so think of the fourth rail bridge, that isn't a solid object but has well‐designed struts and arcs to support it without having to be solid. This allows transmission of loads effectively and supports the areas of maximum stress. 21  Body in Motion MBChB Macroscopic - Cancellous Bone structure ‘Trabecular’ bone Strength without weight Organised along lines of maximum mechanical stress Allows transmission of loads Support areas of maximum stress Strut connections increase strength You can see these struts in detail if you zoom closer up into the bone, and the overall organisation of them can be seen in this diagram on the right, with the different arcs that have developed according to Wolff's Law. 22  Body in Motion Microscopic organisation MBChB Bone structure Woven bone Immature bone Collagen fibres haphazard Not stress-oriented Mechanically weak Rapid production Foetus or fracture Lamellar bone Made by remodelling woven bone Collagen fibres in parallel sheets/lamellae Organised and stress-oriented Osteons Structurally very strong We’ve looked a bit how cortical bone is arrange macroscopically, but if we zoom in a bit further we can see its microscopic organisation. Here we have two different types of bone: woven bone and lamellar bone. Woven bone is immature bone that forms during periods where it needs to be rapidly produced, so during foetal growth or after a fracture. The collagen fibres in woven bone are organised in a haphazard manner and are not stress orientated, meaning that the bone is mechanically weak. The first light microscopy slide in the top left of these images shows woven bone, akin to that of a bird's 23 nest of randomly organised collagen fibres. In contrast, lamellar bone is highly organised bone that stress orientated and is made by remodelling woven bone into the osteonal Haversian system. It’s collagen fibres are in parallel sheets or lamellae, making it a little bit like plywood as shown on the left of this image. It's structurally very strong because of this organised, stress orientated pattern. 23  Body in Motion Composition of Bone MBChB Bone structure 90% of organic component Type I collagen Tensile strength Organic 40% Proteoglycans (osteoid) Compressive strength Non collagenous Matrix proteins Bone proteins Osteocalcin Osteonectin Osteopontin Inorganic 60% Calcium Compressive strength hydroxyapatite IL-1, IL-6, IGF, BMPs So we've looked at the structure and organisation of bone and we’ll now move on to think about the composition of the bone matrix ie, the connective tissue that surrounds the bone cells. The organic part of bone matrix accounts for around 40% and is known as the osteoid. It’s primarily made up of type one collagen, making up 90% of the organic component and this collagen gives the bone its tensile strength. The non‐collagenous proteins are, firstly, the proteoglycans that contribute to compressive strength, and secondly the matrix proteins of osteocalcin, osteonectin and osteopontin. Osteocalcin is the most 24 abundant non‐collagenous protein in the matrix, and it's produced by mature osteoblasts. It promotes mineralization and formation of bone and attracts osteoclasts. Its clinical application is as a marker of bone turnover and can be measured and urine or serum. There're also cytokines and growth factors in the matrix which aid in cell differentiation, activation, growth and turnover. These include Interleukins 1 and 6, insulin‐like growth factor and bone morphogenetic proteins, of which there are many. The inorganic part of bone, which accounts for around 60% of it’s dry mass, is calcium hydroxyapatite, which, along with the proteogylcans in support, gives the bone its compressive strength and is the main form that calcium is stored in the human body. If you’re looking to pick out some specific learning points from this rather horrible slide, I’d say the important facts to take away are that firstly bone has both organic and inorganic components, secondly that Type 1 collagen makes up most of the organic component and gives it tensile strength, and thirdly that the inorganic component is calcium hydroxyapatite which is how calcium is stored in bone and what gives it its compressive strength. 24  Body in Motion Summary MBChB Bone structure Gross organisation of the skeleton Anatomical classification of bones Macroscopic classification Microscopic classification Bone matrix composition So in summary, during this video, we've looked at the gross organisation of the skeleton and then the anatomic, macroscopic and microscopic classification of bone, as well as bone matrix composition. 25  Body in Motion Closing task MBChB Bone structure Answer each of these questions in 50-100 words How can bone be classified? How is bone organised macroscopically? What are the main differences between woven and lamellar bone? Your closing task for this video is to try to write a short answer to each of these questions, which should help you consolidate the important points for your exams and future MSK learning. 26 Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Calcium homeostasis 1  Body in Motion Content MBChB Calcium metabolism Calcium functions and normal levels Locations of activity Overall cycle In this video, we’ll start by looking at how the human body uses calcium and what the normal concentrations are in tissues. We’ll then break down the cycle of calcium homeostasis a bit to make it easier to understand, first by looking at where the activity happens and then tying it all together into the overall homeostatic process. 2  Body in Motion Calcium functions and levels MBChB Calcium metabolism Functions Structural Muscle Ion channels Protein binding Cell signalling In the context of the musculoskeletal system, calcium has 3 very important roles. The first is as the hard structural component of bone, which is the calcium salt hydroxyapatite. Without calcium bones become less dense and less mechanically strong, as can be seen in osteopenia and osteoporosis. 3  Body in Motion Calcium functions and levels MBChB Calcium metabolism Functions Structural Muscle Ion channels Protein binding Cell signalling In skeletal and heart muscle, calcium ions are vital for the contraction cycle. When an action potential reaches the motor endplate, it triggers the depolarisation of the muscles sarcoplasmic reticulum and begins excitation‐contraction coupling. 4  Body in Motion Calcium functions and levels MBChB Calcium metabolism Functions Structural Muscle Ion channels Protein binding Cell signalling The nerve action potential itself relies on the action of voltage gated ion channels, which are particularly sensitive to calcium ion concentration in plasma. Small decreases in serum calcium cause the ion channels to leak sodium, making them hyperexcitable, while small increases mean more calcium binds to these channels, stopping them from depolarizing. Calcium concentrations that are too high or too low therefore interfere with muscle and nerve function resulting in cardiac arrhythmias and muscle tetany or weakness respectively. 5  Body in Motion Calcium functions and levels MBChB Calcium metabolism Functions Structural Muscle Ion channels Protein binding Cell signalling Calcium is also involved in a number of other physiological processes like the protein binding needed for the clotting cascade to function, or the intracellular signalling in, for example, neurotransmitter release. 6  Body in Motion Calcium functions and levels MBChB Calcium metabolism Functions Structural Muscle Ion channels Protein binding Cell signalling Normal levels Total plasma concentration 2.2 - 2.6 mmol/L Intracellular concentration 7000x lower than blood plasma The normal concentration of calcium in the blood can be measured as either TPC, which is what we use clinically, or ionised calcium. Between 35 and 50% of calcium in the blood is bound to protein and a further 5‐10% in complexes with organic acids or phospates. The remaining 50 or 60% is calcium in its ionised form, which can also be measured and is clinically relevant to identify imbalances between ionised and total calcium, for example in disorders with low serum proteins like albumin. The body maintains very tightly controlled compartmentalisation of calcium concentrations, pumping calcium out of cells and keeping an intracellular calcium concentration that can be as much as 7000x lower than blood plasma. This means it’s cell signalling function can be very powerful as even a tiny amount of calcium entering a cell will be detected and set off signalling pathways. 7  Body in Motion Calcium homeostasis MBChB Calcium metabolism Hypo- ↓ Ca2+ PTH calcaemia ↓ Renal Direct OC uptake inhibition OB ↑ renal hydroxylation of vit D IL/MCSF RANKL Calcitonin Ca2+ OC ↑ intestinal ↑ renal activation uptake uptake Slow Intermed Fast Hyper- Thyroid ↑ Ca2+ calcaemia This diagram, represents the process by which the body keeps total serum calcium between 2.2‐2.6 mmol/L. On the left is the response when calcium concentration rises above normal, called hypercalcaemia, and on the right, the response when it drops below normal, called hypocalcaemia. It’s a bit of a daunting looking diagram so let’s split it up a bit and look at where all of this frantic activity happens. 8  Body in Motion Locations of activity MBChB Calcium metabolism Intake and excretion Storage Control One could class the different activities into 3 domains, intake and excretion of calcium, storage of calcium, and processes that monitor, signal and control homeostasis. 9  Body in Motion Locations of activity - Intestines MBChB Calcium metabolism Intake 20mmol per day absorbed 25mmol from diet, 15mmol from bile excretion Net increase of 5mmol Absorbed across brush border Vitamin D dependant (calbindin) Regulated by calcitriol (active form of Vit D) Excretion Bile Excess Ca Let’s start with intake and excretion, which are the processes by which the body first obtains calcium, ie from the diet, excretes excess calcium and then resorbs some of that excreted calcium back up again. In the intestines, a total of about 20mmol of calcium is absorbed per day. Calcium is absorbed across the brush border of intestinal epithelial cells and once in these cells, it is immediately bound to calbindin, which is a vitamin D dependant protein. The active absorption of calcium is regulated by calcitriol, the active form of vitamin D, so you can see that intestinal absorption hinges on having adequate vitamin D, which we’ll look at later. The intestines also excrete calcium via bile. About 15mmol of calcium is excreted into the intestines in bile and when combined with the 25mmol that comes from the normal adult diet, means around 40mmols of calcium pass through the intestines per day. As mentioned a moment ago, 20mmols of this calcium is absorbed or reabsorbed in the case of bile, making for a net increase of 5mmol/day. 10  Body in Motion Locations of activity - Kidneys MBChB Calcium metabolism Filter approx. 250mmol/day and reabsorb 245, for net 5mmol loss Calcitonin INCREASES renal excretion (inhibits reabsorption) PTH Processes Vit D into calcitriol (active form) REDUCES renal excretion The kidneys filter around 250 mmols calcium a day, and reabsorb about 245mmol of this, making a net loss of around 5mmols. When stimulated by calcitonin, this reabsorption is inhibited, meaning more calcium is lost in the urine. PTH has 2 effects on the kidneys, a minor effect of reducing renal excretion, and a major effect of stimulating the processing of vitamin D into calcitriol, it’s activated form. Note the slightly confusing similarity in name to calcitonin. 11  Body in Motion Locations of activity - Bones MBChB Calcium metabolism Storage 99% stored as calcium salts (hydroxyapatite) 1% in ECF Exchange approx. 10mmol/day Turnover OC resorption releases PTH = Indirect stimulation (PTH stimulates RANKL release from OBs) Calcitonin = Direct inhibition In addition to having processes for input and output, a storage site is also needed to keep calcium so it can be added to the circulation, a bit like a warehouse full of stock that supplies a supermarket. 99% of this stored calcium, exists in bones as calcium salts, most commonly hydroxyapatite. The remaining 1% is in the circulation, ECF and cells of the rest of the body. As the bone turns over, around 10mmol of calcium are exchanged with the ECF per day. The release and sequestration of calcium relies on normal bone turnover, with osteoblasts laying down osteoid which is then mineralised with calcium, and osteoclasts resorbing the bone and releasing the calcium back into the ECF. As we’ve learned from talking about bone cells, osteoclasts activity is directly inhibited by calcitonin from the thyroid gland, and is indirectly stimulated when OBs release RANKL under the influence of PTH. 12  Body in Motion MBChB Locations of activity - Control Calcium metabolism Parathyroid gland Has receptors for serum calcium Parathyroid hormone (PTH) Released when LOW serum Ca is detected OBs -> RANKL -> OCs Kidneys Intestine Speaking of Parathyroid hormone, it’s secreted by chief cells within the four parathyroid glands, located on the back of the thyroid gland in the neck. PTH is the most important regulatory hormone of calcium concentration in the bone and blood and is linked to several negative feedback systems that adjust blood calcium ion concentration. A fall in blood calcium ions is detected by the PTH receptors, and PTH synthesis is increased and released into the blood. As we’ve found, PTH acts on the kidneys, the intestines and Obs, indirectly stimulating Ocs to resorb bone. 13  Body in Motion MBChB Locations of activity - Control Calcium metabolism Thyroid gland Has receptors for serum calcium Calcitonin (NOT CALCITRIOL) Parafollicular cells Opposes effects of PTH Directly inhibits OC activity The thyroid gland also has receptors for calcium and releases calcitonin from parafollicular cells in response to high serum calcium. Its action is in opposition to PTH, as it acts to directly inhibit OC activity. 14  Body in Motion Locations of activity - Control MBChB Calcium metabolism Intestines (lipid soluble) Skin (UVB generation) 1,25 (OH)2 D3 Calcitriol VITAMIN D3 Active form of Vit D Liver OC differentiation via 25 hydroxylase RANKL GI absorption 25 (OH) D3 Renal reabsorption Calcitriol In concert with PTH 1,25 (OH)2 D3 Kidneys PTH Low serum Ca 1a hydroxylase As we’ve seen, vitamin D has a very important role to play in calcium metabolism. Vid D3, also called cholecalciferol, is obtained through 2 different routes. First is by absorption of lipid soluble vit D in the intestines, and second by UVB generation in the skin. Once absorbed or synthesed, the Vit D needs to undergo 2 hydroxylations before it reaches its active form. The first happens in the liver, making 25 hydroxyvitamin D, and the second in the kidneys, where it is hydroxylated into calcitiol, or 1‐25 dihydroxyvitamin D. The conversion in the kidneys is stimulated by the action of PTH or low serum calcium. Once active, vitamin D has 3 main actions, stimulating Obs to release RANKL and therefore stimulate Ocs, and to increase absorption and reabsorption in the GI tract and kidneys. 15  Body in Motion Locations of activity - Control MBChB Calcium metabolism Oestrogen Sex hormone produced by the ovaries Inhibits bone resorption Inhibits release of RANKL A final point to mention to do with control is the influence of oestrogen on calcium metabolism. This sex hormone, produced by the ovaries until menopause, acts to inhibit bone resorption by inhibiting the release of RANKL from OBs. As there is less RANKL released, there is reduced OC activity and hence less bone resorption. This protective effect is lost at menopause, leading to increased OC activity and lower bone dentisty. 16  Body in Motion MBChB Overall cycle Calcium metabolism So let’s put everything we’ve learned back into this diagram. 17  Body in Motion MBChB Overall cycle Calcium metabolism Zooming on the bottom left, we see that homeostasis has been interrupted and calcium concentrations have risen to cause a hypercalcaemia. This is detected by the thyroid 18  Body in Motion MBChB Overall cycle Calcium metabolism This is detected by the thyroid 19  Body in Motion MBChB Overall cycle Calcium metabolism Which then releases Calcitonin. The calcitonin acts on the kidneys to reduce renal uptake of calcium, meanin more is lost in the urine, and to inhibit OC activity so less calcium is released into the circulation from bone. 20  Body in Motion MBChB Overall cycle Calcium metabolism The net effect of this is to allow the serum calcium levels to drop, 21  Body in Motion MBChB Overall cycle Calcium metabolism Returning back to normal levels. On the other side of the diagram is the slightly more complicated process to deal with a drop in serum calcium. 22  Body in Motion MBChB Overall cycle Calcium metabolism When the parathyroid gland detects a hypocalcaemia 23  Body in Motion MBChB Overall cycle Calcium metabolism It releases parathyroid hormone. 24  Body in Motion MBChB Overall cycle Calcium metabolism PTH stimulates Obs, which have a PTH receptor on their surface, increasing release of interleukins and macrophage colony stimulating factor, as well as RANK ligand. All of these singaling molecules stimulate OC differentiation and activity so they begin to reabsorb bone. 25  Body in Motion MBChB Overall cycle Calcium metabolism PTH also stimulates hydroxylation of vitamin D into its active form (calcitriol), which happens in the kidneys. PTH and calcitriol then work in concert to increase RANKL release from OBs, and increase the uptake of calcium in both the kidneys and intestine. 26  Body in Motion MBChB Overall cycle Calcium metabolism An important point to note about these 3 pathways for increasing serum Ca, is that they happen at different speeds. Renal uptake happens quickly, intestinal slightly slower and release from bone happens the slowest but with the greatest potential due to the huge stores of calcium in bone. 27  Body in Motion MBChB Overall cycle Calcium metabolism Eventually the calcium levels increase and there is a return to homeostasis. 28  Body in Motion Content MBChB Calcium metabolism Calcium functions and normal levels Locations of activity Overall cycle So in this video, we’ve looked a the functions and normal serum concentrations of calcium then looked in detail at the locations and overall cycle involved in calcium homeostasis. You’ll come back to this complex topic again when you start to study endocrinology. 29  Mr Gavin Brown Senior clinical lecturer Consultant orthopaedic surgeon Body in Motion MBChB Intro to the MSK system Hello and welcome to this introductory lecture in which we’ll begin thinking about the musculoskeletal system and the pathologies that can affect it. 1  Body in Motion Summary MBChB Intro to MSK MSK disease as ‘machine failure’ Conditions affect different age groups MSK disease prevalence MSK disease costs We’ll do this by first exploring the concept of MSK disease as being akin to a failing mechanical machine, which is a simplification that works well to categorise pathologies. We’ll use this concept to the think about how the different ages groups are affected before moving on the explore how common MSK disease is and how much it costs us humans on both a personal and societal level. 2  Body in Motion Modes of failure MBChB Intro to MSK “Machine failure" Bathtub curve Rate of failure Developmental Trauma OA/OP etc Time So let’s start by looking at this machine failure model, which is equating the human body to mechanical machine, that has different modes of failure of the course of its lifespan. We can plot this on a graph with rate of failure on the y‐axis, and time on the x axis representing a patient's lifespan. We can then plot different modes of failure on this, representing the different peaks and troughs of different types of diseases. 3  Body in Motion Modes of failure MBChB Intro to MSK “Machine failure" Bathtub curve Rate of failure Developmental ’Manufacturing error’ Formation and growth Trauma OA/OP etc Time The first line we can draw represents manufacturing errors, and in the human body this would be disorders of formation and growth, which obviously primarily affect patients of paediatric age. 4  Body in Motion Modes of failure MBChB Intro to MSK “Machine failure" Bathtub curve Rate of failure Developmental ’Manufacturing error’ Formation and growth Trauma OA/OP etc Constant (random) failures Time The second line we can draw represents constant random failures, which are primarily related to trauma, but also to things like infection, cancer and other acute diseases. Trauma in particular affects all age groups, but there's a slight variance in the prevalence in each age group, which we'll come on to as we do the various different trauma lectures. 5  Body in Motion Modes of failure MBChB Intro to MSK “Machine failure" Bathtub curve Rate of failure Developmental ’Manufacturing error’ ‘Wear-out failure’ Formation and growth OP, OA, RA etc Trauma OA/OP etc Constant (random) failures Time The third peak or line drawn on the graph represents wearout failures as a machine ages and its parts begin to wear out and systems fail, and this is expressed clinically by diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, et cetera. 6  Body in Motion Modes of failure