Bone Physiology & Calcium Regulation 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Bone Physiology & Calcium Regulation Class Year 1 Course The Body: Movement & Function Code MED 1 - 102 Title Bone Physiology Lecturer Dr. Patrick Walsh Date...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Bone Physiology & Calcium Regulation Class Year 1 Course The Body: Movement & Function Code MED 1 - 102 Title Bone Physiology Lecturer Dr. Patrick Walsh Date November 2024 Learning Outcomes Describe calcium homeostasis and the role of PTH and vitamin D Describe bone structure, list the cells and their functions Explain how bone cells interact in bone remodelling Explain how defective remodelling results in osteoporosis Outline of Lecture 1) Structure of bone a) types of bone b) bone growth 2) Regulation of bone mineralisation a) cells of bone b) bone remodelling 3) Calcium and phosphate regulation a) PTH and Vitamin D 4) Osteoporosis and bone disorders a) osteoporosis b) vitamin D deficiency  Functions and Structure of Bone Bones provide a number of biological functions. These include – support and protection – movement – a Ca2+ (and PO43-) store – a bone marrow store Bone is an mineralised organic matrix The matrix is main type 1 collagen fibres (~90-95%) with some proteoglycans (~5%) – collagen provides the tensile strength – proteoglycans provide the compressive strength In mechanics, compressive strength or compression strength is the capacity of a material or structure to withstand loads tending to reduce size. In other words, compressive strength resists compression, Two Types of Bone The combination of these two types provides mechanical strength despite being lightweight Compact bone – also known as ‘cortical bone’ – dense, stiff structure – low porosity (5-25%) – most human bone is compact (~80%) Trabecular bone – also known as ‘cancellous or spongy bone’ – spongy, light structure – high porosity (up to 70%) Macrostructure of Bone Epiphysis In long bones cortical bone forms the shaft Metaphysis – diaphysis Trabecular bone is found at the ends – epiphysis/metaphysis Diaphysis Between the epiphysis and the metaphysis is the epiphyseal growth plate Growth of the long bones occur at the growth plate until ~18 when it fuses with the metaphysis Bone Growth During fetal life, bones are modelled in cartilage (type 1 collagen) and then mineralised – ossification During childhood/adolescence, cartilage proliferates at the growth plate elongating the long bones – controlled by growth hormone and insulin-like growth hormone (IGF-1) Once growth plate fuses, cartilage proliferation and elongation no longer occur – instead there is vascularisation and ossification of the bone  Microstructure of Cortical Bone The unit of bone growth is the osteon, a series of concentric circles of collagen deposition around a blood vessel – the blood vessels lie in what are called Haversian canals Once laid down the collagen is mineralised with hydroxyapatite – ossification – hydroxyapatite formula: Ca10(PO4)6(OH)2 Outline of Lecture 1) Structure of bone a) types of bone b) bone growth 2) Regulation of bone mineralisation a) cells of bone b) bone remodelling 3) Calcium and phosphate regulation a) PTH and Vitamin D 4) Osteoporosis and bone disorders a) osteoporosis b) vitamin D deficiency Cell Types in Bone There are three main cell types in bone Osteoblasts – promote bone formation – lay down osteoid and initiate mineralisation Osteoclasts, – promote bone reabsorption – remove mineralisation and liberate Ca2+ and PO43- Osteocytes – transfer mineral from inner regions of bone to the growth surfaces Osteoblasts Osteoblasts are modified fibroblasts derived from mesenchymal stem cells The osteoblasts can lay down osteoid (type 1 collagen matrix) and facilitate the ossification of the osteoid Excess osteoblasts are removed but some get embedded in the lining of the new bone and become osteocytes Osteoid: unmineralized bone tissue Osteocytes Osteocytes are derived from osteoblasts – transfer mineral from inner regions of bone to the growth surfaces Osteocytes have cytoplasmic projections into the bone and can sense mechanical load on the bone These projections passes information to the osteoblasts  Osteoclasts Osteoclasts are derived from the macrophage lineage of cells Attracted to and resorb mineralized bone and create resorption pits Solubilise the mineral at low pH, phagocytose the organic matrix – require factors from osteoblasts Indirectly stimulated by PTH that promotes bone reabsorption – remove mineralisation and liberate Ca2+ and PO43- – PTH acts on osteoblasts and their activation ultimately activates osteoclasts Bone Remodelling From maturity, while bone growth has stopped bone turnover does not – adult skeleton remodelled every 10 years – 1 million BMUs operating at any one time (3-4 million BMUs initiated each year) Bones are constantly balancing the mineralisation through activation of osteoblasts and osteoclasts – enables adaptation to mechanical loading – enables fracture healing – prevents “bone fatigue” by continually renewing bone matrix In response to osteocyte signalling, PTH/vitamin D signalling and other growth factors Bone Remodelling Osteocyte detected mechanical strain is relayed to osteoblasts – and also PTH signalling Osteoblasts stimulate NFκB signalling to activate circulating monocytes – increase NFκB activator RANK-L and decrease NFκB inhibitor osteoprotegrin Monocytes become osteoclasts and move to the region to be reabsorbed Growth factors stimulate osteoblast formation leading to laying down of new osteoid for mineralisation – over the ~120 day cycle there is no net loss of bone Bone Remodelling Resorption phase (2 weeks) – bone lining cells pull away from bone surfaces to be resorbed – osteoclasts are attracted to bone surfaces – pockets of bone resorbed by osteoclasts, creation of resorption pits, osteoclast apoptosis Reversal phase (2 weeks) – resorbed bone surface prepared for subsequent bone deposition, formation of cement line Bone Remodelling Formation phase (13 weeks) – resorption of bone releases stored growth factors – osteoblasts attracted to resorption sites and deposit osteoid, which then mineralises – osteoblasts are trapped in bone matrix and become osteocytes or become bone lining cells – cover bone surfaces that are not actively being remodelled Outline of Lecture 1) Structure of bone a) types of bone b) bone growth 2) Regulation of bone mineralisation a) cells of bone b) bone remodelling 3) Calcium and phosphate regulation a) PTH and Vitamin D 4) Osteoporosis and bone disorders a) osteoporosis b) vitamin D deficiency Calcium & Physiological Regulation Ca2+ movement across membranes is important in triggering many physiological mechanisms Some examples are : – neurotransmitter release at a synapse – smooth muscle contraction – heart muscle contraction – secretory mechanisms for hormones – secretory mechanisms for gut enzymes Ca in Body Fluids 2+ Ca2+ is found in three forms ionised (free) - about 45% bound to protein - about 45% bound to small anions - about 10% (e.g. phosphate, citrate and oxalate) In general most physiological functions are mediated by the ionised form (Ca2+) Acid base status can effect levels of bound Ca2+ –  [H+] displaces Ca2+ from protein increasing free [Ca2+] ACIDOSIS –  [H+] promotes Ca2+ binding to protein decreasing free [Ca2+] ALKALOSIS Daily Ca Regulation 2+ Dietary intake 1000 mg Absorption ECF Skeleton Gastrointestinal Tract 350 mg ~ 600 mg 1000 mg 1000 g Secretion 150 mg Urinary Excretion 200 mg Faeces 800 mg Parathyroid Hormone (PTH) The peptide hormone PTH is the major controller of free Ca2+ in the body PTH is released from chief cells in the four parathyroid glands at low plasma [Ca2+] Ca2+ is detected by a membrane bound G-protein receptor coupled to cAMP – Ca2+ decreases cAMP and inhibits PTH release Negative Feedback Controls PTH Control of plasma [Ca ] 2+ 10 0 1, 25 dihydroxycholecalciferol 1,2 5 d ih y d r o x(vitamin y c h o leD3) c a lc if e r o l Max im al S e c r e t io n (% ) ( vit a m in D3 ) 75 50 25 Pa r a t hy r o id ho r m o ne Parathyroid hormone (PTH) 0 1.0 1.5 2.0 2.5 3.0 3.5 Normal [Calcium] = plas m a [ Ca 2 +] ( m m o l/ l) 2.5mmol/L PTH Releases Ca2+ & PO3- from Bone PTH regulates plasma Ca2+ by stimulating bone reabsorption PTH stimulates osteoclasts to promote bone reabsorption – reabsorption of mineral out of bone: i.e. breakdown This is mediated through the increase production of a mixture of cytokines The reabsorption of bone minerals increases the plasma [Ca2+] but also plasma phosphate – bone mineral is hydroxyapatite: Ca10(PO4)6(OH)2 Actions of PTH on the Kidney PTH actions on the kidney modulate the raised plasma Ca2+ and phosphate from the bone reabsorption PTH promotes the reabsorption of Ca2+ – thick ascending limb of the loop of Henle and inhibits phosphate reabsorption – proximal & distal tubule (i.e. promotes phosphate excretion) PTH also stimulates the 1α-hydroxylase enzyme – the key step in the synthesis of the active form of vitamin D Active Vitamin D Production Active form is 1,25 dihydroxycholecalciferol (DHCC) – 1,25 dihydroxy-vitamin D3 also called calcitriol Undergoes 25-hydroxylation in the liver – catalysed by 25-hydoxylase – not a rate-limiting step in production of active form Activation is 1α-hydroxylation in the kidney – catalysed by 1α-hydroxylase – kidney is therefore an important regulatory site Vitamin D is a steroid–like structure so acts on intracellular receptors Active Vitamin D Production. 1 3 5 2 4 6 1. Vitamin D from dietary sources 4. 1α hydroxylation in kidney (key step) to active form 1,25 2. UV stimulated synthesis vitamin D in skin dihydroxy-vitamin D3 3. 25 hydroxylation in the liver 5. Active form promotes Ca absorption from gut 6. Active form promoted mineralisation of bone Actions of Vitamin D on Calcium Ca2+ absorption occurs in the duodenum – Ca2+ absorbed through Ca2+ channels – binds to binding proteins (e.g. calbindin) – actively pumped out at the basolateral side Vitamin D promotes the increased synthesis of these components (Ca2+ channels etc) – as well as phosphate absorption in the gut In kidney tubules, vitamin D promotes Ca2+ and PO43- reabsorption The overall effect of vitamin D is to increase the flux of Ca 2+ and phosphate into bone Outline of Lecture 1) Structure of bone a) types of bone b) bone growth 2) Regulation of bone mineralisation a) cells of bone b) bone remodelling 3) Calcium and phosphate regulation a) PTH and Vitamin D 4) Osteoporosis and bone disorders a) osteoporosis b) vitamin D deficiency Osteoporosis Systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue – bone fragility and susceptibility to fracture 33% of females will suffer a fracture after the age of 50 – post-menopausal – compared to 20% of males will suffer a fracture after the age of 50 Increasing ageing population increases risk Women more likely to suffer a hip fracture than develop breast cancer Vitamin D Deficiency Rickets (in children) – abnormal amounts of unmineralised osteoid – as child grows there is bowing of long leg bones Osteomalacia (in adults) – bone weakness due to unmineralised osteoid – but longitudinal bone growth has been completed – so there is no bowing of the legs Vitamin D Deficiency Daily Ca Regulation 2+ Dietary intake 1000 mg Absorption ECF Skeleton Gastrointestinal Tract 350 mg ~ 600 mg 1000 mg 1000 g Secretion 150 mg Urinary Excretion 200 mg Faeces 800 mg Summary Bone growth stops with the fusing of the epiphyseal plate in the long bones Bone turnover continues throughout life and is mediated by osteoblasts, osteoclasts and osteocytes Vitamin D and PTH control plasma Ca2+ levels and with it bone mineralisation Vitamin D deficiency among other factors can alter Ca2+ availability and decrease bone mineralisation Additional Information Your physiology texts Physiology News (Vitamin D Issue, issue 125, Spring 2022) – https://static.physoc.org/app/uploads/2022/03/25140856/PN125_FINAL_web-1.pdf