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Biochemistry of Bones
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 released 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.
Regulation of 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 Ca 2+ receptor.
• This serpentine receptor is coupled via G protein to phospholipinositide turn
over and is found in many tissues
• In this way when the plasma Ca2+ level is high ,PTH secretion is inhibited and
the Ca2+ is deposited in bones.when it is low, secretion is increased and Ca 2+ is
mobilized from the bones .
• 1, 25 dihydrocholecalciferol acts directlly on the parathyroid gland to decrease
prepro PTH mRNA.
• Increased plasma phosphate stimulates PTH secretion by lowering plasma
Ca2+ and inhibiting the formation of 1, 25 dihydroxy cholecalciferol. 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 7-
dehydrocholesterol by action of sunlight.
• In liver vitamin D3 is converted to 25-hydroxycholecaciferol (25-OH D3).
Mechanism of actions
• The mRNA that is produced in response to 1, 25 dihydroxycholecalciferol
dictate the formation of a family of calbindin D proteins.
• These are member of troponin C super family of Ca 2+ binding proteins that
also includes calmodulin.
• Calbindin Ds are found in human intestine, brain and kidneys.
• In the intestine increased calbindin levels are correlated with increased
calcium transport.
• There is also evidence that 1,25 dihydroxycholicalciferol increases the
number of calcium H ATPase molecules in the intestinal cells ,these are needed to
pump Ca2+ absorption from the intestine ,1,25 dihydroxycholicalciferol facilitates Ca 2+
reabsorption in the kidneys.
• It acts on bones where it mobilises Ca2+ & po4 by increasing the number of
mature osteoclasts.
• It also stimulates osteoblasts, but the net effect is still Ca 2+ mobilization.
Mechanism of actions:
• The formation of 1, 25 dihydrocholicalciferol in the kidneys which is catalyzed
by 1alpha hydroxylase is regulated in feed back fashion by plasma Ca 2+ & PO4.
• Its formation is facilitated by PTH and when the plasma Ca 2+ 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 PO 4 on
alpha 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:
• Serpentine receptors for calcitonin are found in bones and the kidneys.
• This action is direct, and calcitonin inhibits the activity of osteocalsts in vitro.
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.
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:
Excessive parathormone cause bone resorption.
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.