Download J. Clin. Invest.

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The role of estrogen
in
osteoporosis
Advisor: D.r mohiti
By: zahra malekpour
Dep of biochemistry
1394
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Introduction
• Osteoporosis:
 A metabolic bone disorder
 low bone mass and increase in bone fragility
 Bone mass is a determinant of bone strength.
 bone formation peak is at the end of growth.
 Sex hormones as estrogen have important role
in pubertal skeleton growth.
 Estrogen is a regulator bone metabolism.
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Bone Formation
• Bone compounds include:
 support cells: osteoblasts and osteocytes
 remodeling cells: osteoclasts
 non-mineral matrix: collagen & proteins called osteoid
• Ossification (osteogenesis):
a) Synthesis of extracellular organic matrix (osteoid)
b) Matrix mineralization leading to bone formation .
c) Remodeling of bone by the process of resorption and
reformation
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Bone remodeling
• The process of osteoclasts resorb bone and
osteoblasts form new bone.
• Importance of bone remodeling:
Bone enabling to respond and adapt to load induced
strain.
replace old or damaged bone tissue.
maintenance calcium homeostasis.
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Bone remodeling
Bone remodeling unit:
1. Bone resorption:
Activation of osteoclasts
Resorption of minerals and matrix
2. Bone formation:
 Migration and differentiation of preosteoblast
 Matrix formation
 mineralization
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Bone remodeling
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The bone resorption process
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The bone resorption process
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The bone formation process
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The bone formation process
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The Role of estrogen
In
Bone remodeling
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Estrogen
Are as ovarian sex hormones.
Responsible for cellular proliferation and
growth of tissues related to reproduction.
 In premenopausal women ovaries are the most
important source of circulating estrogens.
Placenta also secrets estrogens.
In postmenopausal women and men
extragonadal tissues are the source of estrogen.
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Estrogen
 effects on osteocytes/osteoclasts/osteoblasts
 regulator of bone growth
 regulation of bone remodeling
 Decrease bone resorption
 maintenance of bone formation
 regulation of osteoclasts
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Estrogen receptors
• Classic receptors:
1. Erα: gen in chromosome 6, protein 595 aa
2. Erβ: gen in chromosome 14, protein 530 aa
• Non classic receptors
 G protein-coupled estrogen receptor 1(GPER1) or (GPR30):
 Gen in chromosome 7, protein 375 aa
 present in various cell membrane elements
 respons for rapid estrogen signaling
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Isoforms of Erα & Erβ
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Estrogen signaling pathway
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The role of estrogen in bone remodeling
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The role of estrogen on T cells
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The role of estrogen in bone remodeling
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Health bone & osteoporosis
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Bone formation and age
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Treatment
• Antiresorptive medications:
1. Bisphosphonates:
 nonhydrolyzable analogues of PPi
 bind divalent metal ions, such as Ca2+
 rapidly cleared from the circulation and bind to areas
undergoing osteoclastic resorption
A. The non-nitrogen containing bisphosphonates: are
metabolized in osteoclasts to analogs of ATP, induce
apoptose. (clodronate, etidronate)
B. Nitrogen-Containing Bisphosphonates: Inhibit Farnesyl
Diphosphate Synthase, Prevents the Prenylation
(alendronate, ibandronate, zolendronate)
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Treatment
2. Denosumab
Human monoclonal antibody
Against RANKL
3. selective estrogen receptor modulators(SERM)
(Act as agonist/antagonist of estrogen)
chemical structure
relative level of corepressors and coactivators
type of ER-dependent regulatory sequences; ERE or
other transcription factor binding sites.
ERα/ERβ ratio varies between tissues
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Sites of action of different classes of
drug
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Reference
• Khosla S, Jo Oursler M, G. Monroe D. Estrogen and the skeleton. Trends in
Endocrinology and Metabolism. 2012; 23(11): 576-581.
• Weitzmann M.N, Pacifici R. Estrogen deficiency and bone loss: an inflammatory
tale. J. Clin. Invest. 2006; 116:1186–1194.
• Vrtacniv P, Ostanek B, Mencej-Bedrac S, Marc J. The many faces of estrogen
signaling . Biochemia Medica 2014; 24(3):329–42.
• Cui J, Shen Y, and Li R.Estrogen synthesis and signaling pathways during aging:
from periphery to brain. Trends in Molecular Medicine. 2013; 19(3): 197-209.
• Manolagas S.C, Obrien CH.A. and Almeida M. The role of estrogen and
androgen receptors in bone health and disease. Nat. Rev. Endocrinol. 2013;
9: 699–712.
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Reference
• Singh D, Sanyal s, and Chattopadhyay N. The role of estrogen in bone growth
and formation: changes at puberty. Cell Health and Cytoskeleton. 2011; 3:1–12
• Galea G, Price J, Lanyon L. Estrogen receptors’ roles in the control of
mechanically adaptive bone (re)modeling. Nature(BoneKEy Reports 2). 2013;
413:1-7.
• Roelofs AJ, Thompson k, Gordon SH, et al. Molecular Mechanisms of Action
of Bisphosphonates: Current Status. Clin Cancer Res. 2006;12:6222s-6230s.
• Das S and Crockett JC. Osteoporosis – a current view of pharmacological
prevention and treatment. Drug Design, Development and Therapy. 2013;
7:435–448
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thanks
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