Bone Physiology PDF 2024

Physiology of Bone Dr. Temidayo Omolaoye mbru.ac.ae 3 September 2024 Bone may seem unchanging, in fact, bones are alive and constantly remodeling through time. Learning objectives At the end of this lecture, student should be able to: o Describe bone co...

Physiology of Bone Dr. Temidayo Omolaoye mbru.ac.ae 3 September 2024 Bone may seem unchanging, in fact, bones are alive and constantly remodeling through time. Learning objectives At the end of this lecture, student should be able to: o Describe bone composition and the physiological importance o List the different types of osseous cells and identify their roles in bone health o Describe the endocrine regulation of bone formation, growth, and remodelling o Highlight the roles of exercise, nutrient and aging on bone health o Describe why calcium and vitamin D homeostasis are important for bone health Overview of the skeletal system and bone functions The skeletal system is composed of: o Bones – hard and dense connective tissue that forms most of the adult skeleton, the internal support structure of the body o Cartilages - semi-rigid form of connective tissue, provides flexibility and smooth surfaces for movement o Ligaments - dense connective tissue that connect bones to bones o Tendons - dense connective tissue that connect muscles to bones Bone functions Support, Movement and Protection – the bones give support, facilitate movement, and protect the soft organs of the body. #hard framework of the body Mineral Storage - the bone tissue acts as a reservoir for several minerals important to the functioning of the body, especially calcium, and phosphorus. Bone functions Hormone Regulation: Bones release osteocalcin, a hormone that helps regulate blood glucose levels and fat deposition. Fat Storage - Bones serve as a site for fat storage. There are two types of bone marrow: yellow bone marrow and red bone marrow.  Bone functions Yellow bone marrow contains adipose tissue, and the triglycerides Red bone stored in the adipocytes of this tissue marrow can be released to serve as a source of energy for other tissues of the body. Yellow bone marrow Blood production - Red bone marrow produces blood cells (hematopoiesis). Red blood cells, white blood cells, and platelets are all produced in the red bone marrow. Bone structure- Macroscopic A long bone, for instance, has two main regions: Diaphysis - is the hollow, tubular shaft that runs between the proximal and distal ends of the bone. Inside the diaphysis is the medullary cavity, which is filled with yellow bone marrow in an adult. The outer walls of the diaphysis are composed of dense and hard compact bone, a form of osseous tissue. Bone structure - Macroscopic Epiphysis –the wider section at each end of the bone filled internally with spongy bone (another type of osseous tissue) Red bone marrow fills the spaces between the spongy bone in some long bones Metaphysis: where epiphysis meets the diaphysis during growth the metaphysis contains the epiphyseal plate (site of long bone elongation) Bone lining: Outer lining: Periosteum Inner lining: Endosteum Bone structure – periosteum and endosteum Bone structure – compact bone Compact bone Compact bone is the denser, stronger of the two types of osseous tissue. Strong because it is made up of osteon rings made of collagen and calcified matrix It makes up the outer cortex of all bones and is in immediate contact with the periosteum. Forms 80% of bone tissue Bone structure - compact bone Each ring of osteon is composed of collagen and calcified matrix Bone structure - Spongy bone (Cancellous) Spongy bone (Cancellous) Spongy bone provides balance to the dense and heavy compact bone Contains osteocytes housed in lacunae Osteocytes are found in a lattice-like network of matrix spikes called trabeculae The trabeculae are covered by the endosteum, which can readily remodel them. The spaces in some spongy bones contain red bone marrow, protected by the trabeculae, where hematopoiesis occurs. Bone composition  Bone matrix Bone matrix consists of 1/3rd collagen fibers and 2/3rds calcium phosphate salt. Osteoid – uncalcified collagen secreted by osteoblast The collagen provides a scaffolding surface for inorganic salt crystals to adhere These salt crystals form when calcium phosphate and calcium carbonate combine to create hydroxyapatite. Hydroxyapatite also incorporates other inorganic salts like magnesium hydroxide, fluoride, and sulfate as it crystallizes, or calcifies, on the collagen fibers. The hydroxyapatite crystals give bones their hardness and strength Collagen fibers give calcium phosphate salt a framework for calcification and gives the bone flexibility so that it can bend without being brittle.  Bone cells Osteogenic cells Osteoblasts Osteocytes Osteoclasts Osteoprogenitor cells Bone forming cells Osteoblast differentiate into Bone resorption osteocytes due to calcification Origin Origin process. Origin Mesenchymal cells Mesenchymal cells Origin Monocytes and macrophages lineage Location Location Mesenchymal cells Location Endosteum, cellular layer of the Endosteum, cellular layer of the Location periosteum periosteum, growing portions of Endosteum, cellular layer of the bone Entrapped within their lacunae periosteum, at sites of old, Functions injured, or unneeded bone Functions Functions Differentiate into osteoblasts Functions Role in bone matrix formation Maintain bone as living tissue Responsible for bone Role in calcification Maintain the exchange of resorption during bone calcium between the bone remodeling Role in protein synthesis and extracellular fluid Synthesize and release lysosomal enzymes necessary for bone resorption  Bone formation, growth, and remodeling Bone formation Bone development, also called osteogenesis or ossification begins at sixth or seventh week of embryonic life. Bones are formed in two ways: Intramembranous ossification -Development of compact and spongy bone from mesenchymal cells differentiation into osteogenic cells. Endochondral ossification - Bones develop by replacing hyaline cartilage. In the end, mature bone is the same regardless of the pathway that produces it. Bone growth Bone growth Bone growth occurs at the epiphyseal plate (area of bone elongation). Epiphyseal plate has a layer of hyaline cartilage that continues to get replaced with new bone. Types of bone growth: 1. The longitudinal growth - the process by which bones increase in length. 2. Interstitial growth - contributes to the expansion and maintenance of cartilage tissue within the bone (growth by adding to the free surface of bone). Bone remodeling Bone undergoes constant remodeling → Resorption of old or damaged bone takes place on the same surface where osteoblasts lay new bone to replace that which is resorbed. Injury, exercise, and other activities lead to remodeling. Even without injury or exercise, about 5 to 10% of the skeleton is remodeled annually just by destroying old bone and renewing it with fresh bone. Bone remodeling/bone metabolism This process is essential for maintaining bone strength, repairing micro- damages, and regulating calcium and phosphate homeostasis. Bone metabolism involves two primary cellular activities: Bone resorption by osteoclasts Bone formation by osteoblasts. 20 Phases of bone remodeling Phases of Bone Remodeling: 1. Activation: Bone remodeling begins with the activation of osteoclast precursors, by signals such as RANKL (Receptor Activator of Nuclear factor Kappa-B Ligand) produced by osteocytes and osteoblasts. This leads to the differentiation of osteoclasts. Phases of bone remodeling 2. Resorption: Mature osteoclasts adhere to the bone surface and create a sealed resorption pit. They secrete hydrochloric acid and proteolytic enzymes (e.g., cathepsin K) to dissolve the bone mineral and degrade the organic matrix. This phase typically lasts about 2-4 weeks. Phases of bone remodeling 3. Reversal: Following resorption, osteoclasts undergo apoptosis, and mononuclear cells appear on the resorbed surface. These cells prepare the site for new bone formation by cleaning up the bone surface and depositing a thin layer of unmineralized matrix. Phases of bone remodeling 4. Formation: Osteoblasts are recruited to the resorbed site, where they lay down new osteoid. This new matrix then undergoes mineralization, incorporating calcium and phosphate to form new bone. The formation phase is slower than resorption and can take several months. 5. Quiescence: Once bone formation is complete, the surface is covered by bone lining cells, and the remodeled bone enters a resting phase until the next remodeling cycle is initiated. Quiescence = dormancy or inactivity Endocrine regulation of bone growth The important hormones for bone growth include: Growth hormone (GH) Insulin-like growth factor 1 (IGF-1) Insulin-like growth factor 2 (IGF-2) Insulin Thyroid hormone Testosterone (in male) Estrogen (in female) Endocrine regulation of bone growth Growth hormone Promotes bone lengthening by stimulating maturation and cell division of chondrocytes in the epiphyseal plates continuous widening of the plates and provision of more cartilaginous material for bone formation *Molecules that stimulate cell division are called mitogens Exerts mitogenic effect indirectly through the mediation of mitogenic hormone IGF-1 *IGF-1 synthesis and release by the liver is mediated by growth hormone Stimulates bone cells to secrete IGF-1 where it functions as an autocrine or paracrine substance Autocrine = A cell produces a substance that affects itself by binding to its own receptors. Paracrine = A cell produces a substance that affects nearby cells by binding to their receptors. Endocrine regulation of bone growth Insulin-like growth factor 1 (IGF-1) Upon stimulation of bone cells by GH to secrete IGF-1, it is believed that IGF-1 and GH interact on the epiphyseal plates to allow bone growth. Proposed mechanism on interaction: GH stimulate chondrocytes precursor cells to differentiate into chondrocytes During differentiation, the cells begin to secrete IGF-1 and also become responsive to IGF-1 IGF-1 then acts as an autocrine and paracrine substance (along with blood- borne IGF-1) to stimulate the differentiating chondrocytes to undergo cell division Endocrine regulation of bone growth Thyroid hormone Thyroid hormone facilitates the synthesis of growth hormone T3 directly stimulates: Chondrocyte differentiation Growth of new blood vessels in developing bones Responsiveness of bone cells to other growth factors such as fibroblast growth factor. Endocrine regulation of bone growth Insulin Stimulates growth during fetal life Stimulates postnatal growth by stimulating the secretion of IGF-1 Testosterone Stimulates growth at puberty Stimulates the secretion of GH Enhances epiphyseal line in males Endocrine regulation of bone growth Estrogen/Estradiol Stimulates growth at puberty Stimulates the secretion of GH Enhances epiphyseal line in females Hormones and bone health Hormones that affect osteoblasts i.e favoring bone formation and increasing bone mass Growth hormone T3 Insulin Testosterone (in male) Estrogen (in female) Calcitriol (active form of vitamin D) Calcitonin Hormones and bone health Hormones that affect osteoclasts i.e favoring bone resorption Parathyroid hormone (PTH) Cortisol Thyroxine Prostaglandins Interleukin-1 Hormones and bone health Summary Hormones that affect bone health Hormone Role Growth hormone Increases length of long bones, enhances mineralization, and improves bone density Triiodothyronine Stimulates bone growth and promotes synthesis of bone matrix Sex hormones Promote osteoblastic activity and production of bone matrix; responsible for adolescent growth (Testosterone, spurt; promote conversion of epiphyseal plate to epiphyseal line Estrogen) Calcitriol Stimulates absorption of calcium and phosphate from digestive tract Parathyroid hormone Stimulates osteoclast proliferation and resorption of bone by osteoclasts; promotes reabsorption of calcium by kidney tubules; indirectly increases calcium absorption by small intestine Calcitonin Inhibits osteoclast activity and stimulates calcium uptake by bones Exercise and bone health Lack of mechanical stress causes bones to lose mineral salts and collagen fibers, and thus strength. Mechanical stress stimulates the deposition of mineral salts and collagen fibers. This is why astronauts traveling for long-term space mission can lose approximately 1 to 2% of their bone mass per month. The internal and external structure of a bone will adapt in response to increasing or decreasing stress, optimizing its size and weight to suit the level of activity it experiences. This is why people who exercise regularly have thicker bones than people who are more sedentary. It is also why a broken bone in a cast atrophies while its contralateral mate maintains its concentration of mineral salts and collagen fibers. The bones undergo remodeling as a result of forces (or lack of forces) placed on them. The role of nutrients on bone tissue Nutrient and bone health Nutrients that affect bone health Nutrient Role in bone health Needed to make calcium phosphate and calcium Calcium carbonate, which form the hydroxyapatite crystals that give bone its hardness Vitamin D Needed for calcium absorption Supports bone mineralization; may have synergistic Vitamin K effect with vitamin D Magnesium Structural component of bone Fluoride Structural component of bone Reduces inflammation that may interfere with Omega-3 fatty acids osteoblast function Calcium metabolism Calcium is not only the most abundant mineral in bone, but also the most abundant mineral in the human body. Calcium ions are needed for bone mineralization and for tooth health. They are needed for the regulation of heart rate and strength of contraction Needed for blood coagulation, contraction of smooth and skeletal muscle cells, and the regulation of nerve impulse conduction. Calcium metabolism Calcium is available in the blood in three forms: Free ionized calcium (about 45% depending on albumin levels) – found freely in plasma. Calcium bound to plasma proteins (45%) Calcium complexed with anions (phosphate, bicarbonate, citrate; e.g calcium bicarbonate; 10%) Based on the above classifications, blood calcium levels can also be investigated in two ways: A total calcium test - measures both free and bound calcium. It's the type of blood calcium test doctors order most often. An ionized calcium test measures only free calcium. Calcium metabolism The normal level of calcium in the blood is between 8.6 and 10.2 milligrams per deciliter (mg/dL). When the body cannot maintain this level, a person will experience hypo- or hypercalcemia Hypocalcemia: Characterized by abnormally low levels of calcium (10.2mg/dL) May lead to the nervous system being underactive, which results in lethargy, sluggish reflexes, constipation and loss of appetite, confusion, and in severe cases, coma. As important as calcium is to the body, it cannot be produced endogenously and thus cannot be absorbed without the help of Vitamin D Vitamin D metabolism First Vitamin D (cholecalciferol) hydroxylation in the Liver → conversion to 25- Hydroxyvitamin D (Calcidiol) Cholecalciferol is transported to the liver, where it undergoes hydroxylation by the enzyme 25-hydroxylase to form 25- hydroxyvitamin D [25(OH)D], also known as calcidiol. 25(OH)D is the major circulating form of vitamin D and is considered the best indicator of vitamin D status in the body. It has a half- life of about 2-3 weeks. Vitamin D metabolism Second hydroxylation in the kidneys → conversion to 1,25-Dihydroxyvitamin D (Calcitriol) The 25(OH)D is then transported to the kidneys, where it undergoes a second hydroxylation by the enzyme 1-alpha-hydroxylase to form 1,25- dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol. Calcitriol is the biologically active form of vitamin D and has a short half-life of about 4-6 hours. It is responsible for most of the physiological effects of vitamin D. Vitamin D functions in relation to bone Biological Functions of Active Vitamin D (Calcitriol) 1. Calcium and Phosphate Homeostasis: o Intestinal Absorption: Calcitriol increases the intestinal absorption of calcium and phosphate by upregulating the expression of calcium-binding proteins (e.g., calbindin) and transporters in the intestinal mucosa. o Bone Resorption: Calcitriol works synergistically with PTH to stimulate osteoclast differentiation and activity, promoting the release of calcium and phosphate from bone. o Renal Reabsorption: Calcitriol enhances the reabsorption of calcium and phosphate in the kidneys, reducing their excretion in urine. 2. Bone Health: o Calcitriol promotes bone mineralization by maintaining adequate levels of calcium and phosphate in the blood, which are essential for the formation of hydroxyapatite crystals in bone. Vitamin D metabolism The metabolism of vitamin D is tightly regulated by several factors to maintain calcium and phosphate balance: 1. Parathyroid Hormone (PTH): o When blood calcium levels are low, PTH is secreted by the parathyroid glands. o PTH stimulates the activity of 1-alpha-hydroxylase in the kidneys, increasing the conversion of 25(OH)D to calcitriol, o Thereby raising blood calcium levels by enhancing calcium absorption from the intestine, reabsorption in the kidneys, and mobilization from bones. 2. Calcium and Phosphate Levels: o Low calcium levels stimulate PTH secretion, enhancing calcitriol production. o High phosphate levels inhibit 1-alpha-hydroxylase activity, decreasing calcitriol synthesis. Vitamin D metabolism 3. Fibroblast Growth Factor 23 (FGF23): o FGF23, produced by osteocytes in response to high phosphate levels, inhibits 1- alpha-hydroxylase activity in the kidneys and reduces calcitriol production o Thereby reducing intestinal phosphate absorption and lowering serum phosphate levels. 4. Calcitriol Feedback: o High levels of calcitriol can inhibit further production of itself by downregulating 1-alpha-hydroxylase and upregulating 24-hydroxylase, which converts calcidiol and calcitriol to their inactive forms (24,25-dihydroxyvitamin D and 1,24,25- trihydroxyvitamin D, respectively). Calcium homeostasis Major players: PTH Calcitriol Calcitonin Aging and bone tissue Osteoporosis is characterized by a decrease in bone mass It occurs when the rate of bone resorption exceeds the rate of bone formation, a common occurrence as the body ages. While osteoporosis can involve any bone, it most commonly affects the proximal ends of the femur, vertebrae, and wrist Questions?