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The role of estrogen in

osteoporosisAdvisor: D.r mohiti

By: zahra malekpour

Dep of biochemistry1394

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• 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.

Introduction

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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 osteoclastsResorption 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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effects on osteocytes/osteoclasts/osteoblasts regulator of bone growth regulation of bone remodeling Decrease bone resorption maintenance of bone formation regulation of osteoclasts

Estrogen

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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 aapresent in various cell membrane elements respons for rapid estrogen signaling 15

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

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 structurerelative level of corepressors and coactivatorstype 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