Gore-9. Physiol of PTH, calcium, bone.pdf

1 By the end of of this unit, you will learn and understand: ¡ ¡ ¡ Bone and bone remodeling Calcium homeostasis Endocrine control of calcium homeostasis § Parathyroid hormone (PTH) § Vitamin D – active form is 1,25-(OH)2-D3 § Fibroblast growth factor (FGF)-23 § Calcitonin 2 ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡...

1 By the end of of this unit, you will learn and understand: ¡ ¡ ¡ Bone and bone remodeling Calcium homeostasis Endocrine control of calcium homeostasis § Parathyroid hormone (PTH) § Vitamin D – active form is 1,25-(OH)2-D3 § Fibroblast growth factor (FGF)-23 § Calcitonin 2 ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Osteoblasts: bone building cells, deposit new bone Osteoclasts: bone dissolving cells Osteoid: the organic extracellular matrix that makes up bone Cartilage: similar to bone but not calcified. Epiphysis: knob at the end of long bone Diaphysis: cylindrical shaft Epiphyseal plate: layer of cartilage separating the epiphysis from the diaphysis in growing bone Osteocytes: osteoblast derived cells, the most abundant cell type in bone, important for calcium homeostasis Chondrocytes: cartilage cells in the outer edge of the epiphyseal plate that divide and multiply during bone growth Periosteum: connective tissue sheath covering the outer bone Cortical (compact) bone: outer bone compartment Trabecular (cancellous) bone: inner bone compartment Ossification: process of bone being laid down during growth or remodeling Bone marrow: site of blood cell production ACG: Here they are again! (from previous unit) 3 § Outer compartment: Cortical (compact) bone - ~80% of skeletal mass, and gives bone much of its strength. § Inner compartment – Trabecular (cancellous) bone, ~20% of mass. Made up of interconnected plates called trabeculae – sites of active remodeling. 4 Bone is living tissue composed of organic extracellular matrix – osteoid Bone is impregnated with hydroxyapatite crystals that are largely Ca3(PO4)2 salts. These stores may be mobilized when plasma Ca++ falls. Thus, bone remodeling is involved in Ca++ homeostasis. Remodeling occurs via bone deposition/resorption. This maintains skeletal strength and health. The human skeleton turns over every ~10 years. 5 Osteoclasts: responsible for bone resorption (breakdown) Osteoblasts: responsible for laying down new bone 6 Osteoblasts derive from mesenchymal precursors in bone marrow stroma RANK-L (34 a.a. peptide) is made by osteoblast and bone marrow stromal cells. Its receptor, RANK, resides on osteoclast precursors. RANK enhances osteoclast differentiation, decreases osteoclast cell death. Osteoclasts derive from hematopoietic precursors. OPG is a secreted “decoy receptor” protein, produced by marrow cells. Osteoclasts secrete enzymes that dissolve bone; this also releases calcium Osteoblasts mineralize the bone matrix by depositing hydroxyapatite crystals to produce bone. 7 7 THE BOTTOM LINE: Osteoblasts make two products, RANK-L and OPG. Their balance determines the outcome on bone mass. When OPG is low/RANKL high, the osteoclast pathway is favored, and bone mass decreases. When OPG is high/RANKL low, the osteoblast pathway is favored, and bone mass increases. Under which circumstance will calcium be liberated? 8 8 ¡ Neuromuscular excitability Ø Hypocalcemia (ê Ca++ )èé Na+ influx èResting potential closer to threshold è éneuromuscular excitability è Spasm. Ø Hypercalcemia (é Ca++) causes ê neuromuscular excitability and cardiac arrhythmias (life threatening). ¡ Excitation-contraction coupling in cardiac and smooth muscle ¡ Stimulus-secretion coupling § Ca++ triggers exocytosis of neurotransmitters and peptides. ¡ Excitation-secretion coupling § Pancreatic β-cells: membrane depolarizationèé Ca++ entry èinsulin secretion. ¡ Maintenance of tight junctions between cells ¡ Clotting of blood: Calcium is a cofactor in clot formation. 9 ¡ The endocrine system regulates plasma concentrations of inorganic electrolytes: Na+, K+, Ca++, PO43- ¡ The main regulators are § Parathyroid hormone (PTH) § Calcitonin § 1,25-(OH)2-D3 (what we call Vitamin D) ¡ 99% of calcium is crystalline form in skeleton and teeth. § Bone is a reservoir of calcium. ¡ The remaining 1% is in extracellular fluid, of which: § ~47% is bound to plasma proteins (mainly albumin) and not available § ~47% is ionized (“serum ionized calcium”) § ~6% is complexed to organic ions (citrate, phosphate, bicarbonate) ▪ The pool of serum ionized calcium controls cellular functions 10 Hormone Major stimulus Origin Parathyroid hormone Low serum [Ca++] Effect on serum [Ca++] PTH gland Vitamin D Low serum (1,25-(OH)2-D3) [Ca++], low serum [phosphate], PTH Made in skin, then metabolized in liver, then kidney Fibroblast growth factor23 (FGF-23) High serum [phosphate] Osteocytes in bone matrix Calcitonin High serum [Ca++] Parafollicular C cells of thyroid gland 11 Effect on serum [phosphate] Osteocyte Osteoblast Osteocytic– osteoblastic bone membrane Osteoblast Osteoclast Blood vessel Mineralized bone Outer surface Central canal Bone fluid Canaliculi Lamellae Gap junction (a) Osteocytic–osteoblastic bone membrane Calcium exchange across osteocytic-osteoblastic bone membrane 12 § Secreted by parathyroid glands § Peptide hormone (115 amino acid preproPTH, cleaved to mature PTH(1-84) § Half-life 10 min § Metabolized by liver, metabolites are cleared by the kidney § Highly responsive to alterations in serum calcium concentrations – changes within seconds ▪ Low serum Ca++ à Stimulate PTH secretion ▪ High serum Ca++ à suppresses PTH synthesis and secretion 13 PTH producing cells express an extracellular calcium-sensing receptor, CaSR. ¡ When [Ca++] is high, the CaSR is activated, inhibiting the release of PTH. ¡ When [Ca++] is low, the CaSR is inactive, and PTH is released. Chronic hypocalcemia stimulates proliferation of the PTH gland, leading to hyperplasia. 14 ¡ Type 1 receptor, most important in mediating PTH effects on Ca++ (bone, kidney) § Expressed on osteoclasts and osteoblasts § Recognizes PTH and PTH-related peptide (PTHrP) – the latter is clinically important for some cancers ¡ Type 2 receptor, expressed on other tissues (brain, pancreas, testis, placenta) § Specific to PTH. 15 § PTH stimulates calcium § § § § 16 release from bone (enhances osteoclast activity by stimulating RANK-L) Stimulates reabsorption of calcium in the kidney Inhibits phosphate reabsorption, promotes phosphate excretion Stimulates production of 1,25-(OH)2-D3, which in turn increases intestinal calcium reabsorption As Ca++ goes up, negative feedback is exerted on the PTH gland § Vitamin D is a prohormone produced in the dermis in § § § § § response to UV-B exposure Metabolized to active forms first in liver, then kidney. Active hormone is 1,25-(OH)2-D3. PTH stimulates the synthesis of Vit D, thereby integrating the stimulation of calcium homeostasis. (Vit D enhances intestinal reabsorption of calcium) Vit D synthesis is stimulated by hypocalcemia and hypophosphatemia. Vit D synthesis is inhibited by hypercalcemia, hyperphosphatemia, FGF-23, and low PTH. § RDA (NIH, 2020) – 400 IU (up to 1 yr), 600 IU (1-70 yr), 800 IU (70+ yr) § Vitamin D supplements contain a prohormone in the US, and are metabolized to 1,25-(OH)2-D3 https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ 17 Vitamin D receptor is a member of the steroid hormone receptor family – derives from cholesterol. In the intestine, it stimulates active intestinal transport of Ca++ in the duodenum, enabling calcium absorption. In bone, it regulates osteoblast/osteoclast function to favor the osteoclast pathway, through RANK/RANK-L. This helps to increase plasma [Ca++]. Vit D also promotes intestinal absorption of phosphorus. 18 Plays a central role in regulating phosphate homeostasis. (FGF-23 is stimulated when phosphate is high; its job is to restore serum phosphate to physiological levels) Physiology: Primarily produced by osteocytes in bone matrix. Effects are mediated by FGF receptors and their co-receptor transmembrane protein, klotho. 19 § Peptide hormone (32 a.a.) produced by parafollicular C cells of thyroid gland § C cells are