The role of estrogen in osteoporosis Advisor: D.r mohiti By: zahra malekpour Dep of biochemistry 1394

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.

Bone Formation Bone compounds include: Ossification (osteogenesis): support cells: osteoblasts and osteocytes remodeling cells: osteoclasts non-mineral matrix: collagen & proteins called osteoid Ossification (osteogenesis): Synthesis of extracellular organic matrix (osteoid) Matrix mineralization leading to bone formation . Remodeling of bone by the process of resorption and reformation

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.

Bone remodeling Bone remodeling unit: Bone resorption: Bone formation: Activation of osteoclasts Resorption of minerals and matrix Bone formation: Migration and differentiation of preosteoblast Matrix formation mineralization

Bone remodeling

The bone resorption process

The bone resorption process

The bone formation process

The bone formation process

The Role of estrogen In Bone remodeling

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.

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

Estrogen receptors Classic receptors: Non classic receptors Erα: gen in chromosome 6, protein 595 aa 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

Isoforms of Erα & Erβ

Estrogen signaling pathway

The role of estrogen in bone remodeling

The role of estrogen on T cells

The role of estrogen in bone remodeling

Health bone & osteoporosis

Bone formation and age

Treatment Bisphosphonates: Antiresorptive medications: nonhydrolyzable analogues of PPi bind divalent metal ions, such as Ca2+ rapidly cleared from the circulation and bind to areas undergoing osteoclastic resorption The non-nitrogen containing bisphosphonates: are metabolized in osteoclasts to analogs of ATP, induce apoptose. (clodronate, etidronate) Nitrogen-Containing Bisphosphonates: Inhibit Farnesyl Diphosphate Synthase, Prevents the Prenylation (alendronate, ibandronate, zolendronate)

Treatment 2. Denosumab 3. selective estrogen receptor modulators(SERM) 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

Sites of action of different classes of drug

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.

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

thanks