Download ROLE OF PARATHYROID HORMONES, CALCITONIN + VIT

ROLE OF PARATHYROID HORMONES, CALCITONIN + VIT-D IN BONE METABOLISM
LECTURE OBJECTIVES
At the end of lecture the student should be able to;
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Describe chemical composition of bone
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Explain the role of osteoblasts and osteoclasts cells in bone mineralization and bone
resorption .
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Justify that parathyroid hormone, vitamin D and calcitonin effect the bone metabolism .
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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
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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
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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)
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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
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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
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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
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Type I Collagens appears to be necessary, with mineralization.
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Acidic phosphoproteins such as bone sialo protein acting as sites of nucleation.
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These proteins contain motifs e.g poly-Asp and poly Glu stretches, that bind Calcium and
may provide an initial scaffold for mineralization.
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Some macro molecules such as certain proteoglycans and glycoproteins, can act as
inhibitors of nucleation.
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Many factors are involved in the regulation of bone metabolism.
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Some stimulate Osteoblasts e.g Parathyroid hormone, 1,25 diydroxy Cholecalicferol
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Other inhibit them e.g. Corticosteriods, Parathyroid hormone & 1,25 dihydroxy
cholecalciferol also stimulate Osteoclasts, where as calcitonin & estrogen inhibit them.
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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
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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.
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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.
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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
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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 .
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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
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