Veltri Bone and Joint Disorders.pdf

PCOL 838b Bone and Joint Disorders Alison K. Veltri, PhD 1 Contents • Parathyroid Glands • Vitamin D/Calcium • Bones • Disorders of Calcium Metabolism • Other Conditions • Osteoporosis/Osteomalacia 2 Parathyroid Glands • Typically have 4 • 30-40 mg ea • Regulate calcium homeostasis through sy...

PCOL 838b Bone and Joint Disorders Alison K. Veltri, PhD 1 Contents • Parathyroid Glands • Vitamin D/Calcium • Bones • Disorders of Calcium Metabolism • Other Conditions • Osteoporosis/Osteomalacia 2 Parathyroid Glands • Typically have 4 • 30-40 mg ea • Regulate calcium homeostasis through synthesis and secretion of parathyroid hormone (PTH) 3 Parathyroid Glands Histology • Adipose • Chief cells • Small (4-8 µm) • Central nuclei • Produce PTH • Oxyphil cells • Large (6-10 µm) • Appear after puberty • Unknown function Image Source 4 Parathyroid Hormone (PTH) • Controls calcium homeostasis • Increases plasma Ca2+ • Very sensitive to small changes in serum calcium concentration • Travels via blood • Targets bone, kidneys, intestines 5 PTH Receptor • Type I • PTH • PTH-related peptide (PTHrP) • Type II • PTH • Binding activates adenylyl cyclase • cAMP • DAG/IP3 • PKC • Intracellular calcium mobilization 6 Ca2+-Sensing Receptor (CaSR) • GPCR (plasma receptor) • Ligand = calcium ( Ca2+) • Expressed in many cells • Kidneys, thyroid C cells, brain 7 Physiologic Functions of Calcium 8 Key Hormones for Calcium Balance • Regarding importance to adults: 1. PTH 2. Calcitriol 3. Calcitonin 9 PTH and Plasma Ca2+ 1. PTH mobilizes calcium from bone 2. PTH enhances renal reabsorption of calcium 3. PTH indirectly increases intestinal absorption of calcium 10 Calcitriol (1, 25dihydroxycholecalciferol/Vitamin D3) • Production is regulated at the kidneys by PTH • Ca2+ . PTH secretion calcitriol synthesis • Calcitriol is the primary hormone responsible for enhancing Ca2+ uptake from the small intestine • Facilitates renal reabsorption of Ca2+ • Helps mobilize Ca2+ out of bone 11 PTH, Calcitriol, and Phosphate Homeostasis • Phosphate is second key ingredient in hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂ ] of bone • Most phosphate in body is found in bone • Major effect of PTH on phosphate handling: promote phosphate excretion • Inhibition of sodium-dependent phosphate transport • Occurs in proximal tubule 12 Fibroblast Growth Factor-23 (FGF-23) • Regulates serum phosphate homeostasis, vitamin D metabolism, bone mineralization 13 Calcitonin • Released by C cells of thyroid • Acts directly on osteoclasts • Blocks bone resorption induced by hormones like PTH and Vitamin D • Has actions that are opposite the actions of PTH • Released when plasma Ca2+ increases 14 Bone Structure • Cortical (compact) • • • • Outside 80% skeletal mass Gives strength Slowly remodeled • Trabecular (cancellous) • Inside • 20% skeletal mass • Rapidly remodeled 15 Osteocytes • Bone cells • Mechanoreception and transduction of loading signals that induce changes in bone remodeling • Osteoblasts • Osteoclasts 16 Osteoblasts • Bone-forming • Under influence of PTH and Vitamin D3 • Have PTH receptors • Secrete osteocalcin, osteonectin, enzymes, collagen fibers, proteoglycan • Osteoid formation • Concentrate calcium/phosphate into vesicles • Enzymes secreted by osteoblasts free calcium and phosphate • Precipitate into hydroxyapatite crystals that interact with osteoid 17 Osteoclasts • Bone-dissolving • Large, mobile, multinucleate cells • Derived from macrophage lineage • No PTH receptors • Formation requires M-CSF (macrophage colony-stimulating factor) and other signals • Contain central region • Secretes acid and proteases • Dissolves hydroxyapatite matrix and collagen 18 Bone Resorption 19 Control of Bone Remodeling • PTH effects mediated through osteoprotegrin (OPG) and RANK-L (osteoclast differentiation factor) 20 Bone Remodeling • Net zero bone balance 21 1, 25-(OH)2D3 (Vitamin D) • VDR is member of steroid receptor superfamily of DNA-binding nuclear receptors • Primary targets: intestines and bone • Most essential action: stimulate active intestinal calcium transport in the duodenum • Deficiency à bone mineralization defects (rickets) • Related to calcium and phosphate delivery to sites of mineralization problems 22 23 Calcium Homeostasis Disorders • Primary hyperparathyroidism • Hypercalcemia • Most common cause: chief cell adenomas • Treat with surgery 24 Calcium Homeostasis Disorders • Hypoparathyroidism • Caused by injury or neck surgery • Calcium decreases, phosphate increases • Treat with calcium/vitamin D supplements, PTH therapy (Natpara), dietary changes 25 Medullary Carcinoma (Thyroid) • Causes hypercalcitoninemia (high calcitonin) • 20% have genetic association (multiple endocrine neoplasia MEN2A/MEN-2B) • Hereditary mutations in RET proto-oncogene • Treat with thyroid surgery 26 Osteoporosis • Bone resorption > bone deposition • Metabolic disorder • Most common in women after menopause • Risk factors: small and thin body type, postmenopausal age, smoking, poor diet, low dietary calcium intake 27 Osteoporosis • Most important etiologic factor: gonadal steroid deficiency • Estrogen deficiency à increased bone turnover and enhanced resorption 28 Bisphosphonates • Ex: risedronate (Actonel), alendronate (Fosamax), ibandronate (Boniva), zoledronic acid (Reclast), and pamidronate (Aredia) • Oral or IV formulations • MOA: induce osteoclast apoptosis, suppress bone resorption 29 PTH Derivatives • Ex: teriparatide (Forteo) • MOA: stimulated new bone formation • Consists of first 34 AA of PTH • Injectable only 30 Osteomalacia • Bone mineralization defect • In children = rickets • Caused by vitamin D deficiency, phosphate deficiency, inherited alkaline phosphatase deficiency, drugs • Rarely vitamin D deficiency 31 The End 32