Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
ROLE OF PARATHYROID HORMONES, CALCITONIN + VIT-D IN BONE METABOLISM LECTURE OBJECTIVES At the end of lecture the student should be able to; • Describe chemical composition of bone • Explain the role of osteoblasts and osteoclasts cells in bone mineralization and bone resorption . • Justify that parathyroid hormone, vitamin D and calcitonin effect the bone metabolism . • Relate the hormonal imbalance with various diseases (Rickets, Osteomalacia, Osteoporosis, Osteogenesis imperfecta). BONE COMPOSITION The matrix – 40% organic • Type 1 collagen (tensile strength) • Proteoglycans (compressive strength) • Osteocalcin/Osteonectin • Growth factors/Cytokines/Osteoid – 60% inorganic • Calcium hydroxyapatite The cells – osteo-clast/blast/cyte/progenitor BONE MATRIX: The Organic Material Bones contain both organic and inorganic material. The organic material is mainly protein Type – I Collagen, comprising 90-95% of organic material. Type – V collagen is also present in small amounts, as are number of non- collagen proteins . The inorganic component is mainly crystalline hydroxyapatite Ca10(PO4)6(OH)2 along with sodium, magnesium, carbonate and fluoride. Approximately 99% of body calcium is contained in bones. Bone is dynamic structure that under goes continuing cycles of remodeling, consisting of resorption followed by deposition of new bone tissues. BONE METABOLISM • Relates to bone – Formation and growth – modeling/remodeling • Maintenance of bone shape and consistency – healing BONE FORMATION OSSIFICATION (prenatal) BONE FORMATION OSSIFICATION (prenatal) BONE FORMATION OSSIFICATION (prenatal) BONE FORMATION OSSIFICATION (prenatal) • • • BONE MODELLING REMODELLING Bone remodeling is a continuous process of bone resorption and bone formation for the purpose of maintaining normal bone mass: Bone Deposition is the apposition or formation of new bone as a normal physiologic process. Bone Resorption is a process involving the breakdown of bone by specialized cells known as osteoclasts OSTEOCLASTS • • • • Osteoclasts are multinucleated cells, possess an apical membrane domain, exhibiting a ruffled border that plays a key role in bone resorption. A proton translocating ATPase expels protons across the ruffled border in to resorption area. This Lowers the Local PH to 4.0 or less, thus increasing the solubility of hydroxyapatite & allowing demineralization to occur. Lysosomal acid proteases are realeased that digest the new accessible matrix proteins. OSTEOBLASTS • • • • Osteoblasts are mono-nuclear cells, synthesize most of proteins found in bone as well as various growth factors & cytokines. They are responsible for the deposition of new bone matrix (Osteoid) and its subsequent mineralization. Osteoblasts Control mineralization by regulating the passage of calcium & phosphate ions across their surface membranes. The Latter contains alkaline phosphatase, which is used to generate phosphate ions from inorganic phosphate. OSTEOCLASTS & OSTEOBLASTS • Type I Collagens appears to be necessary, with mineralization. • Acidic phosphoproteins such as bone sialo protein acting as sites of nucleation. • These proteins contain motifs e.g poly-Asp and poly Glu stretches, that bind Calcium and may provide an initial scaffold for mineralization. • Some macro molecules such as certain proteoglycans and glycoproteins, can act as inhibitors of nucleation. • Many factors are involved in the regulation of bone metabolism. • Some stimulate Osteoblasts e.g Parathyroid hormone, 1,25 diydroxy Cholecalicferol • Other inhibit them e.g. Corticosteriods, Parathyroid hormone & 1,25 dihydroxy cholecalciferol also stimulate Osteoclasts, where as calcitonin & estrogen inhibit them. • • • • • • • • FACTORS EFFECTING BONE GROWTH, DEVELOPMENT AND REPAIR Nutrition Exposure to sunlight Hormonal secretions Physical exercise / stress VITAMIN D Promotes absorption of calcium from the small intestine Maintain blood levels of calcium and phosphate for bone formation, mineralization, growth, and repair Improves muscle strength and immune function Reduces inflammation ROLE OF PARATHYROID HORMONE • • • • Human PTH is a linear polypeptide that contains 84 Amino acid residues. It is synthesized as part of larger molecule containing 115 a.a residues (pre-pro-PTH). PARATHYROID HORMONE (contd..) Pre-pro-PTH enters into endoplasmic reticulum, where leader sequence is removed from the amino terminal to form the 90 amino acids polypeptide pro-PTH Six additional amino acids residues are removed from the amino terminal of pro PTH in the golgi apparatus and the 84 amino acids polypeptide PTH is packaged in secretory granules and released as the main secretory product of the chief cells. • • • • • • • • • • • • • ACTIONS OF PARATHYROID HORMONE Tends to increase serum Calcium Levels Acts directly on bones to increase bone resorption & mobilize Ca 2+. Increases phosphate excretion in urine This phosphaturic action is due to a decrease in reabsorption of phosphate in the proximal tubules. Increases reabsorption of Ca2+ in the distal tubules, although Ca2+ excretion is often increased in hyper-parathyroidism because the increase in the amount filtered overwhelms the effect on reabsorption. Increases the formation of 1,25 dihydroxy Cholecalciferol, and this increases Ca2+ absorption from intestine. PTH stimulates both osteoclasts and osteoblasts with the predominating effect on osteoclasts so that more Ca2+ is mobilized from bone. REGULATION OF PTH SECRETION Circulating ionized calcium acts directly on the parathyroid gland in a negative feedback fashion to regulate the secretion of PTH. The key to this regulation is a cell membrane Ca2+ receptor. This serpentine receptor is coupled via G protein to phospholipinositide turn over and is found in many tissues At high plasma Ca2+ level PTH secretion is inhibited and the Ca2+ is deposited in bones. At low levels, secretion is increased and Ca2+ is mobilized from the bones 1,25 dihydrocholecalciferol acts directlly on the parathyroid gland to decrease pre-pro PTH mRNA. • • • • • • • • • • • • Increased plasma phosphate stimulates PTH secretion Magnesium is required to maintain normal parathyroid secretory response Impaired PTH release along with diminished target organ responses to PTH accounts for the hypocalcemia that occasionally occurs in magnesium deficiency ROLE OF VITAMIN D The active transport of Ca2+ & PO4 from intestine is increased by metabolite of vitamin D. Vitamin D3 which is also called cholecalciferol is produced in skin from 7dehydrocholesterol by action of sunlight. In liver vitamin D3 is converted to 25-hydroxycholecaciferol(25-OH D3). It is than converted to 1,25 dihydroxycholecalciferol (calcitriol) in the proximal tubules of kidney. ACTIONS Tends to increase serum calcium levels Increases Ca2+ absorption from the intestine Facilitates Ca2+ reabsorption in the kidneys. Mobilizes Ca2+ and PO4, from bones by increasing the number of mature Osteoclasts. It also stimulates osteoblasts, but the net effect is still Ca2+ mobilization. MECHANISM OF ACTIONS • • • • • • • • • • • • • • • • • Stimulate the formation of calbindin D proteins. Member of troponin C super family of Ca2+ binding proteins that also includes calmodulin. Calbindin D is found in intestine , brain and kidneys In the intestine increased calbindin levels are correlated with increased calcium transport. Facilitates Ca2+ reabsorption in the kidneys. It acts on bones: mobilizes Ca2+ & PO4 by increasing the number of mature osteoclasts. It also stimulates osteoblasts, but the net effect is still Ca2+ mobilization. The formation of 1,25 dihydrocholicalciferol in the kidneys which is catalyzed by 1-α hydroxylase It is regulated in feed back fashion by plasma Ca2+ & PO4. Its formation is facilitated by PTH and when the plasma Ca2+ level is low, PTH secretion is increase. When the plasma Ca2+ level is high ,little 1,25 dihydroxycholicalciferol is produced the production of 1,25 dihydroxycholecalciferol is also increased by low and inhibited by high plasma PO4 levels, by the direct inhibitory effect of PO4 on 1-α hydroxylase CALCITONIN Human calcitonin has M.W 3500 and contains 32 amino acid residues . Calcitonin is not secreted until the plasma calcium level reaches approximately 9.5mg/dl and that above this calcium level . Plasma calcitonin is directly proportionate to plasma calcium . Beta –adrenergic agonists ,dopamine and estrogen ,also stimulate calcitonin secretion . • • • • • • Gastrin ,CCK, glucagon and secretin have all been reported to stimulate calcitonin secretion. ACTIONS OF CALCITONIN Receptors for calcitonin are found in bones and the kidneys. Calcitonin lowers the circulating calcium and phosphate levels. It exerts its calcium lowering effect by inhibiting bone resorption. This action is direct, and calcitonin inhibits the activity of osteocalsts in vitro. It also increases Ca2+ excretion in Urine. DISORDERS INVOLVING BONES Rickets: It is due to deficiency of Vitamin D during childhood. The full-blown condition in children is characterized by weakness and bowing of weight bearing bones, dental defects and hypoclacemia. OSTEOPORESIS: It is generalized progressive reduction in bone tissue mass per unit volume causing skeletal weakness. The ratio of mineral to organic elements is unchanged in the remaining normal bone. It is mostly associated with advancing age and the menopause due to estrogen deficiency HYPERPARATHYROIDISM: Excess parathormone cause bone resorption. OSTEOMALACIA: It is due to deficiency of vitamin D during adulthood, results from demineralization of bones, especially in women who have little exposure to sunlight, often several pregnancies. OSTEOGENESIS IMPERFECTA: It is brittle bone disease characterized by abnormal fragility of bones. Over 90% of patients with osteo-genesis imperfecta have mutation in genes. REFERENCES Harper (Biochemistry) 29th edition *************************************************************************************