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BIOCHEMISTRY BONE METABOLISM MSK BLOCK SYSTEM

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BIOCHEMISTRY BONE METABOLISM MSK BLOCK SYSTEM Nabil Bashir October 1st, 2009 Bone Inorganic (67%) Hydroxyapatite 3 Ca10(PO4)6(OH)2 There is some amorphous calcium ... – PowerPoint PPT presentation

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Title: BIOCHEMISTRY BONE METABOLISM MSK BLOCK SYSTEM


1
BIOCHEMISTRYBONE METABOLISMMSK BLOCK SYSTEM
  • Nabil Bashir
  • October 1st, 2009

2
Bone
  • Inorganic (67)
  • Hydroxyapatite 3 Ca10(PO4)6(OH)2
  • There is some amorphous calcium phosphate
  • Organic (33) component is called osteoid
  • Type I collagen (28)
  • Non-collagen structural proteins (5)
  • Proteoglycans
  • Sialoproteins
  • Gla-containing proteins (gamma carboxyglutamate)
  • Phosphoproteins
  • Bone specific proteins osteocalcin, osteonectin
  • Growth factors and cytokines (Trace)
  • Bone undergoes continuous turnover or remodeling
    throughout life
  • About 20 of bone is undergoing remodeling at any
    one time

3
Osteoblast and Osteoclast Function
  • Osteoblasts
  • Bone formation
  • Synthesis of matrix proteins
  • Type I collagen
  • Osteocalcin
  • Others
  • Mineralization
  • Activation of osteoclasts via RANKL production
  • Osteoclasts
  • Bone resorption
  • Degradation of proteins by enzymes
  • Acidification
  • RANK is activated by RANKL, and this leads to
    cells differentiation to osteoclasts

4
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5
PTH and Osteoblastogenesis
6
Osteoclast Mediated Bone Resorption
7
Osteoclastogenesis RANK/RANKL/OPG axis
RANK Receptor activator of nuclear factor
(NF)-kB RANKL RANK ligand OPG Osteoprotegerin
(cytokine) Activating factors M-CSF, IL-6etc.
ASBMR Bone Curriculum
8
Osteoclastogenesis
Activating factors cause the lining cells to
produce RANKL, and then the RANK of the
preosteoclasts binds with the RANKL and the forms
multinucleated activated osteoclasts (10-20 fused
cells, called polykaryons) OPG also binds with
RANKL, preventing the preosteoclast RANK from
binding
ASBMR Bone Curriculum
9
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10
Hormonal Control of Resorption Pro-resorptive
Most of the proresorptive factors upregulate mRNA
expression of RANKL in osteoblasts
Boyle et al, Nature 2003
11
Hormonal Control of Resorption Anti-resorptive
Boyle et al, Nature 2003
12
Genetic Mutations
Boyle et al, Nature 2003
What would an OPG knock-out mouse look like?
13
CALCIUM PHOSPHORUS HOMEOSTASIS
  • PTH,
  • VIT D,
  • CALCITONIN,
  • ESTROGENS

14
BLOOD
1,25 D
PTH
1,25 D
Absorption
Ca?PO4
PTH 1,25 D
INTESTINE
1,25 D
?
Figure 1. Control of blood Ca2 and PO43- matrix
KIDNEY
1,25(OH)2D3 increases intestinal and renal
absorption of phosphate to help promote bone
mineralization
calcitonin (CT) can counteract the effect of PTH
on bone resorption estrogen (E2) counteracts
effects of PTH and 1,25(OH)2D3 on bone resorption

PTH, in response to low serum Ca, increases
plasma Ca by increasing bone resorption, and
renal reabsorption of Ca
1,25(OH)2D3, in response to low serum Ca,
increases plasma Ca by increasing intestinal
absorption, bone resorption, and renal
reabsorption of Ca
PTH prevents hyperphosphatemia, which could be
caused by the PTH effect on bone resorption, by
inhibiting renal reabsorption of phosphate
PTH activates the hydroxylation of 25(OH)D3 to
the active 1,25(OH)2D3 form
15
Bone Remodeling
  • Osteoclasts dissolve bone
  • Large multinucleated giant cells
  • Osteoblasts produce bone
  • Have receptors for PTH, CT, Vitamin D, cytokines,
    and growth factors
  • Main product is collagen
  • When osteoblasts become encased in bone, they
    become osteocytes

16
Figure 3. Control of bone remodeling by PTH
Osteoblast Bone constructor
Osteoclast Bone destructor
? ?cAMP ? ?PKA
Gs
PTH
ODF osteoclast differentiating factor
osteoblast
Osteoprotegerin receptor decoy
ODF receptor
MOP
MOP monocytic osteoclast progenitor cells
Differentiation and fusion
M-CSF macrophage colony stimulating factor
17
Figure 3. Control of bone remodeling by PTH and
calcitonin
Osteoblast Bone constructor
Osteoclast Bone destructor
? ?cAMP ? ?PKA
Gs
PTH
IL-6
IL-6 other cytokines
inactivation
?
CT
Gs
??PKA ??cAMP ?
activation
ODF
Calcitonin secreted by thyroid C-cells in
response to hypercalcemia
CT gene can yield calcitonin gene-related peptide
(CGRP) if processed differently (alternative mRNA
splicing) CGRP a potent vasodilator
18
Specific receptors in intestine, bone,
kidney Ca Intestinal absorption Renal
reabsorption Bone resorption PO4 Intestinal
absorption Renal reabsorption
Figure 4. Photobiosynthesis of vitamin D3 and
its metabolism
19
Osteoblast Bone constructor
Osteoclast Bone destructor
VDR receptor
Nucleus
RXR receptor
mRNA
1,25D3
Chemotaxis
MOP
Figure 7. Control of bone remodeling by
1,25(OH)2D3
20
Osteoblast Bone constructor
Osteoclast Bone destructor
? ?cAMP ? ?PKA
Gs
PTH
IL-6
IL-6 other cytokines
inactivation
?
mRNA
CT
Gs
??PKA ??cAMP ?
3
activation
ODF
Osteocalcin
1,25D3
osteoblast
PTH, 1,25D3
?
ODF receptor
Gla
Ca2
MOP
Osteoblast
Differentiation and fusion
osteoclast
c-FMS receptor
Figure 8. Control of bone remodeling by PTH and
1,25(OH)2D3 and antagonism of their effects by
estrogen and androgen
M-CSF
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