bone repair calcium homeostasis Witchel 2023-04-01 (1).ppt

Structures Remodel The Physiology of Bone [email protected] Path Ca2+ Calcium Clinical Professor Harry Witchel What makes bone strong? What causes osteoporosis? 1 Structures Remodel Learning Outcomes • Structures & Cells of bone:  activities & activators • Remodelling of bone Clinical...

Structures Remodel The Physiology of Bone [email protected] Path Ca2+ Calcium Clinical Professor Harry Witchel What makes bone strong? What causes osteoporosis? 1 Structures Remodel Learning Outcomes • Structures & Cells of bone:  activities & activators • Remodelling of bone Clinical • Calcium homeostasis (endocrine) Path Ca2+ • Clinical: Calcium  Mechanical stress in bone remodelling  Introduction to Drugs for Osteoporosis  Pathologies of Bone Remodelling: Osteopetrosis  Repair of Bone Fractures  Role of parathyroid hormone, vitamin D and calcitonin • Pathologies of Calcium Regulation 2 Structures Remodel Clinical Recommended Reading • Tortora (14th ed.)  International Student Version  Chapter 6 (Bone Tissue) • Guyton & Hall (13th ed.) Path Ca2+ Calcium  More detailed text book  Chapter 79  Calcium & bone 3 Increasing Bone Mineral Density Path Ca2+ Calcium Clinical Remodel Structures Healthy Bone Physiology is a balance Bone Resorption Bone Formation Imbalance this side leads to Imbalance this side Osteoporosis Osteopetrosis 4 Structures Remodel Classifications of Bone Structure Classifications  Long bone  Flat bone Clinical • Macroscopic  Cortical Bone  Cancellous (spongy) • Spicules, trabeculae Path Ca2+ Calcium • Microscopic Cancellous - Macroscopic  Lamellar • Osteons  Woven • Immature • Disorganised Woven - Microscopic 5 living cells and acellular matrix Structures Osteoclasts Extracellular Matrix (osteoid) Path Ca2+ Clinical 3 principle cell types Calcium Remodel composition of bone Osteocytes osteoblasts Mostly extracellular matrix 6 Structures Remodel Clinical Calcium 3 principle cell types osteoblasts – on surface bone, produce protein component acellular matrix – regulate bone growth and degradation osteocytes – quiescent mature cells embedded in bone matrix. They maintain bone. osteoclasts – responsible for bone degradation and remodelling Organic – cells and proteins Path Ca2+ Inorganic – minerals, eg Ca2+ & PO4- (hydroxyapatite) • bone dominated by extracellular matrix – few cells 7 Communication system between cells immobilised in bone matrix Lamellae Structures Clinical Remodel Haversian System in Lamellar Bone Path Ca2+ Calcium Ground substa between cells As opposed to “woven bone” shown in x- HS runs Parallel to bone and along long axis of bone 8 Structures Remodel Clinical Calcium Path Ca2+ Osteocytes arise from Osteoblasts • From mesenchyme  From precursor cells in bone marrow stroma • Osteoblasts are post-mitotic  Most osteoblasts will undergo apoptosis  Number of osteoblasts  with age • A low % of osteoblasts will become osteocytes locked in lacuna 9 Structures Remodel Clinical Osteoclasts Function: Resorption Multinucleate 40-100 micrometer in diameter. 15-20 closely packed oval-shaped nuclei. Can proliferate Electron micrograph of an osteoclast Path Ca2+ Calcium Same precursor as monocytes (haematopoietic stem)  Phagocytose (bone matrix & crystals)  Secrete Acids  Secrete proteolytic enzymes from lysosomes ruffled border = where bone resorption occurs 10 Structures Bone constituents  Extracellular matrix is 70% minerals  Plus abundant proteins and sparse cells  High compressive strength and tensile strength Path Ca2+ Calcium Clinical Remodel Bone is unique acellular elements of bone collagen fibres – protein, flexible but strong hydroxyapatite – mineral, provides rigidity calcium/phosphate crystals > 50 % Similar to reinforced concrete collagen = rods crystals = cement 11 Structures Remodel Clinical Calcium extracellular matrix includes gycosaminoglycans Glycosaminoglycans  “fluffy” & protective  long polysaccharides  Highly negative  Attract Water  Repel each other  Resists compression Path Ca2+  Abundant in Cartilage Proteoglycans = protein containing GAGs These are another set of organic molecules in bone ground 12 Structures Remodel Clinical growth factors: also in ECM Growth factors are suspended in matrix They are revealed by osteoclast action Path Ca2+ Calcium Which leads to proliferation & mineralisation bone remodelling = bone turnover = the activation-resorption-formation sequence These are another set of organic molecules in bone ground 13 Structures Remodel Osteoclasts resorb bone Osteoblasts deposit bone In Howship’s Lacuna Onto pre-existing bone Osteoclas t Osteoblas t Path Ca2+ Calcium Clinical Bone Cells remodel bone Bone Remodelling is Very active Lays down bone in different directions 14 Structures Path Ca2+ Calcium Clinical Remodel Activation Resorption Remineralisation sequence 15 Structures Remodel Clinical Bone formation • bone forms either as compact or cancellous and by either intramembranous or endochondral bone formation – Module 102 Path Ca2+ Calcium • Please see review lecture slides 16 Please review definitions as this is core knowledge and could be on exam Structures Remodel Clinical Calcium Path Ca2+ Factors governing remodelling • two major factors  Recurrent mechanical stress  calcium homeostasis • Plasma calcium is essential in maintaining structural integrity of skeleton • 2nd half of this lecture 17 Structures Remodel Clinical Calcium Path Ca2+ mechanical stress — strengthens bone inhibits bone resorption promotes deposition Surface osteoblasts & osteocyte network detect stresses Without weight bearing bone rapidly weakens skeleton reflects forces acting on it E.g. Bed rest Lack of Gravity (astronauts) 18 Structures Remodel Bisphosphonates • For osteoporosis Path Ca2+ Calcium Clinical • E.g. Alendronate alendronat e pyrophosphat e • inhibit osteoclast-mediated bone-resorption • related to inorganic pyrophosphate  the endogenous regulator of bone turnover  Accumulate on bone & ingested by osteoclasts • Interfere with osteoclasts metabolism IMPORTANT Integrate this info with osteoporosis 19 • Encourage osteoblast formation of bone  Teriparatide  portion of human parathyroid hormone (PTH)  Intermittent application activates osteoblasts Structures Path Ca2+ Calcium Clinical Remodel Other Drugs for Osteoporosis: mechanisms more than osteoclasts • Prevent osteoclast maturation  Denosumab • Monoclonal Antibody that targets RANKL IMPORTANT Integrate this info with osteoporosis 20 Structures Remodel Clinical Calcium Path Ca2+ Osteopetrosis (Autosomal Recessive) Molecular Mechanism  Osteoclasts cannot remodel bone  Defective Vacuolar proton pump or  Defective Chloride channel Excess bone growth  Bone growths at foramina press on nerves  Brittle (dense) bones  Blindness  Deafness  Severe anaemia Osteo – petrosis = “bone like stone” See also arterial calcification (info in notes) 21 Carbonic Anhydrase Rxn H2O + CO2  H2CO3  H+ + HCO3- Structures Path Ca2+ Calcium Clinical Remodel Not required: How Osteoclasts Secrete Acid 22 Structures Remodel Clinical Calcium Path Ca2+ Phases of Fracture Healing: Stages 1 & 2 Reactive Phase: Haematoma & Inflammation Blood cells enter wound Haematoma forms Inflammatory cells invade Granulation tissue formed Aggregation of Blood vessels Fibroblasts Bone Precursor cells arrive from Periosteum Soft Cartilage Callus Soft Callus formation Woven bone (or hyaline cartilage) join the pieces Woven bone near BVs Fibrocartilage further away 23 Structures Remodel Phases of Fracture Healing: Stages 3 & 4 Hard Callus Formation Lamellar bone replaces woven bone Clinical Remodeling Trabecular bone replaces (endochon.) lamellar bone Path Ca2+ Calcium Original bone shape Soft Cartilage Callus Compact bone formed where appropriate Duration: upper body 2-3 weeks, lower body > 4 weeks 24 Structures Remodel Clinical Calcium Path Ca2+ Hormones of calcium regulation • PTH – parathryoid hormone, parathormone  Parathyroid chief cells  Increases plasma Ca2+ • Vitamin D: 1,25-di-OH cholecalciferol (calcitriol)  Made in stages: Skin  Liver  Kidney  Increases plasma Ca2+ • Calcitonin  Made by thyroid C cells  “tones down” blood calcium • Calcium goes into bone • Used as a treatment for osteoporosis 25 Structures Remodel Overview: Requirements for Healthy Bone Growth • Diet  Calcium  Calories Clinical • Vitamin D  Diet  Sun (makes precursor of Vitamin D) Path Ca2+ Calcium • Hormones: Gonadal & bone  Testosterone in male,  Oestrogen in Females • Exercise & bone loading • Genetics  60-70% of peak bone mass is determined genetically 26 Structures Clinical Remodel How PTH stimulates resorption via osteoblasts CLAS T CLAS T PT H = Decoy receptor Path Ca2+ Calcium PTHR BLAS T Effects of Intermittent PTH ≠ Effects of Continuous PTH 27 Structures Remodel Clinical Calcium Path Ca2+ In class question • Draw Plasma a negative feedback showing Kidney increasesloop Ca resorption at DCT Ca Enterocytes increase calbindin  Ca absorption increases mobilises Ca calcium to plasma how transiently lowBone plasma triggered by lactation can be corrected physiologically by the action of PTH lactation NEGATIVE FEEDBACK Perturbation: Low plasma Ca2+ Chief cells release PTH Calcium sensitive receptor in parathyroid chief cells detect low calcium 28 Structures Vitamin D: production & activation Calcium Clinical Remodel SKIN Cholecalciferol (Vitamin D3) 25-OH cholecalciferol 1, 25-di-OH cholecalciferol (calcitriol = active vitamin D)  Calbindin in gut enterocytes   Intestinal absorption of Path Ca2+ Ca2+ review from module 203  Ca2+ reabsorption in kidneys  Plasma Ca2+ 29 Structures Remodel Vitamin D • Increases intestinal Ca2+ absorption  Increases calbindin Clinical • Stimulates kidneys to reabsorb calcium • stimulates osteoclasts indirectly Path Ca2+ Calcium  via osteoblasts  This is a comparatively weak effect • Vitamin D facilitates bone remodelling and thus increases serum Ca2+ 30 Structures Remodel Causes of Low Plasma Calcium Loss  Pregnancy  Lactation Path Ca2+ Calcium Clinical  Kidney dysfunction Low Intake  Insufficient ingestion of Calcium  Rickets (low vit D) Parathyroid dysfunction 31 Structures Remodel Clinical Chronic Hypocalcaemia Results in • Skeletal deformities • Increased tendency toward bone fractures Path Ca2+ Calcium • Impaired growth • Short stature (adults less than 5 feet tall) • Dental deformities Rickets can be caused by chronic hypocalcaemia 32 Structures Remodel Clinical Calcium Acute Hypocalcaemia  Excitability Mnemonic B – Bleeding A – Anaesthesia Chvostek’s Sign D – Dysphagia (Latent Tetany) C – Convulsions A – Arrhythmias T – Tetany Trousseau’s Sign S – Spasms and stridor Carpopedal spasm Path Ca2+ (Latent Tetany) DiGeorge Syndrome http://www.nejm.org/doi/full/10.1056/ Core NEJMicm074227 33 Structures Remodel Clinical Calcium Path Ca2+ Low Plasma Calcium  excitability • Effect seems paradoxical  i.e. counter-intuitive • Hypocalcaemia makes membranes “more excitable” and “less stable”  Sodium is more able to leak through it  Explains latent tetany and its signs • Hypercalcaemia paradoxically reduces excitability  By making membranes more stable 34 Structures Remodel Clinical Calcium Hypercalcaemia Signs & Symptoms: Decreased Excitability Can be asymptomatic Reduced excitability  Esp. Constipation  Depression + other psychiatric Abnormal heart rhythms  Short QT interval, ST segment disappears  Widened T wave Path Ca2+ Severe hypercalcaemia • Coma • Cardiac arrest 35 Structures What You Have Learned Calcium Clinical Remodel • Balance of resorption & mineralisation • Cells: shape, secretion, fxn • ECM constituents • Drugs for Osteoporosis: mechanisms  Interfere with Osteoclast  Metabolism, Differentiation, Activity of Secretions Path Ca2+ • Review calcium homeostasis  Uptake, loss, mobilisation • Symptoms: calcium & osteopetrosis 36