SCLEROSTIN

By Irsalan Asif and Shareen Bibi

CONTENT

Structure of Sclerostin Mechanism of action Regulation of SOST gene/ Sclerostin Hormonal regulation Potential therapies

STRUCTURE OF SCLEROSTIN

• Product of SOST gene

• Has Cysteine knot structure as a focal point• Three loop like structures attached to the knot• On Loop 2 there is a Heparin Sulfate binding site

present. Localisation of a protein molecule?• Antibody Binding site on loop 2. Inhibitory action?

• Protein binding site on Loop 2 and 3.

Veverka V, Henry A, Slocombe P, Ventom A, Mulloy B, Muskett F et al. Characterization of the structural features and interactions of sclerostinmolecular insight into a key regulator of Wnt-mediated bone formation. Journal of Biological Chemistry. 2009;284(16):10890--10900. MoesterM, Papapoulos S, Lowik C, Van Bezooijen R. Sclerostin: current knowledge and future perspectives. Calcified tissue international. 2010;87(2):99--107. Williams B. Insights Into the Mechanisms of Sclerostin Action in Regulating Bone Mass Accrual. Journal of Bone and Mineral Research. 2014;29(1):24--28.

Veverka V, Henry A, Slocombe P, Ventom A, Mulloy B, Muskett F et al. Characterization of the structural features and interactions of sclerostin molecular insight into a key regulator of Wnt-mediated bone formation. Journal of Biological Chemistry. 2009;284(16):10890--10900.

MECHANISM OF SCLEROSTIN

ACTION

• Antagonist of Wnt pathway (Signal transduction pathway)• Wnt protein binds to LPR5/6 (Transmembrane receptor)• This leads to activation of B Catenin inside Osteoblast• B Catenin (transcriptional coactivator) accumulates in the

nucleus and initiates transcription.• Can be broken down by glycogen synthase inside the cell if

Wnt protein is inhibited.

Moester M, Papapoulos S, Lowik C, Van Bezooijen R. Sclerostin: current knowledge and future perspectives. Calcified tissue international. 2010;87(2):99--107. Weivoda M, Oursler M. Developments in Sclerostin Biology: Regulation of Gene Expression, Mechanisms of Action, and Physiological Functions. Current osteoporosis reports. 2014;12(1):107--114. Sapir-Koren R, Livshits G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?. Osteoporos Int. 2014;25(12):2685-2700.

Lewiecki E. Sclerostin monoclonal antibody therapy with AMG 785: a potential treatment for osteoporosis. Expert Opin BiolTher. 2011;11(1):117-127.

MECHANISM OF SCLEROSTIN ACTION -LPR5/6

6 bladed propeller unit, the first propeller unit binds to Sclerostin

Sclerostin does not compete with Wnt for binding site

Wnt cannot bind to LPR5/6 if Sclerostin is bound

Leads to break down of B Catenin inside cell, no gene expression

Mutations in Sclerostin and LPR5/6 are associated with changes in human bone mass

Moester M, Papapoulos S, Lowik C, Van Bezooijen R. Sclerostin: current knowledge and future perspectives. Calcified tissue international. 2010;87(2):99--107. Weivoda M, Oursler M. Developments in Sclerostin Biology: Regulation of Gene Expression, Mechanisms of Action, and Physiological Functions. Current osteoporosis reports. 2014;12(1):107--114. Sapir-Koren R, Livshits G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?. Osteoporos Int. 2014;25(12):2685-2700.. Krause C, Korchynskyi O, de Rooij K, Weidauer S, de Gorter D, van Bezooijen R et al. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signalling pathways. Journal of Biological Chemistry. 2010;285(53):41614--41626.

EFFECT OF MECHANO-

SENSATION ON SCLEROSTIN

• At high stress levels, Sclerostin reduced.

• More Osteoclast recruitment and no inhibition of Wnt pathway, greater gene expression.

• Sclerostin levels increased with low stress levels.• Increased Osteoclast apoptosis and inhibition of

Wnt pathway, lower gene expression

Robling A, Niziolek P, Baldridge L, Condon K, Allen M, Alam I et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. Journal of Biological Chemistry. 2008;283(9):5866--5875. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J et al. Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/beta-Catenin Signaling. Journal of bone and mineral research. 2009;24(10):1651--1661. Weivoda M, Oursler M. Developments in Sclerostin Biology: Regulation of Gene Expression, Mechanisms of Action, and Physiological Functions. Current osteoporosis reports. 2014;12(1):107--114.

Sapir-Koren R, Livshits G. Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption–formation cycles?. Osteoporos Int. 2014;25(12):2685-2700.

Moester M, Papapoulos S, Lowik C, Van Bezooijen R. Sclerostin: current knowledge and future perspectives. Calcified tissue international. 2010;87(2):99--107.

EFFECT OF AGE ON SCLEROSTIN

• Older age leads to increased Sclerostin levels• Positive correlation between Sclerostin levels

and age• May be due to increased Osteocytes and not

age

Williams B. Insights Into the Mechanisms of Sclerostin Action in Regulating Bone Mass Accrual. Journal of Bone and Mineral Research. 2014;29(1):24--28. M, Papapoulos S, Lowik C, Van Bezooijen R. Sclerostin: current knowledge and future perspectives. Calcified tissue international. 2010;87(2):99--107.

EFFECT OF OSTEOCYTE

FUNCTION ON SCLEROSTIN

• Increase RANKL expression• May lead to other proteins being expressed

e.g.: Carbonic anhydrase• Sclerostin has a catabolic effect through the

promotion of Osteoclasts by Osteocyte derived RANKL

Wijenayaka A, Kogawa M, Lim H, Bonewald L, Findlay D, Atkins G. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6(10):25900. Kogawa M, Wijenayaka A, Ormsby R, Thomas G, Anderson P, Bonewald L et al. Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. Journal of Bone and Mineral Research. 2013;28(12):2436--2448. Weivoda M, Oursler M. Developments in Sclerostin Biology: Regulation of Gene Expression, Mechanisms of Action, and Physiological Functions. Current osteoporosis reports. 2014;12(1):107--114.

HORMONAL REGULATION OF SCLOROSTIN

OestrogenDifferent types of

hormones that regulate Sclerostin

Parathyroid hormone

Prostaglandin E2 and hypoxia

Glucacorticoids

Calcitonin Cytokins

Zfp467

Ephrin B2

Osterix

HOW THE PARATHYROID HORMONE REGULATES SCLEROSTIN

PTH plays a central role in the maintenance of calcium homeostasis

Chronic elevation of PTH increases osteoclast formation

PTH stimulates bone formation by suppressing Sclerostin expression

Inhibition through the cyclic AMP/PKA pathway.

Prostaglandin E2 acts through two receptors EP2 and EP4

In response to mechanical loading, leads to bone formation is due to changes in prostaglandin E2.

Hypoxia inhibits sclerostin by increasing regulation of beta-catenin signalling.

Prostaglandin E2 and Hypoxia

SEX STEROIDS

Oestrogen and testosterone are known to regulate bone growth and bone remodelling.

Sclerostin levels in postmenopausal women are higher compared to premenopausal women.

Oestrogen action occurs by down regulating MEF2 and Sclerostin.

CALCITONIN (CT)

Calcitonin receptors are present on osteoclast cells, inhibiting osteoclast resorption

Sclerostin production is increased by calcitonin.

significantly inhibits PTH anabolic effects, increasing Sclerostin levels

GLUCOCORTICOID

Bone cells have receptors for glucocorticoid, and it inhibits bone formation therefore increases bone resorption.

Glucocorticoid depresses bone formation through the effect on Wnt/beta-catenin pathway

Recently some data has shown that patients treated with high doses of glucocorticoids have increased levels of sclerostin and decreased levels of Dkk-1.

DISEASES ASSOCIATED WITH SCLEROSTIN

Sclerosteosis: is an autosomal recessive disorder

Decreased Sclerostioin = Increased bone formation

Van Buchem’s disease: is an autosomal recessive disease that occurs due to bone overgrowth.

Sclerostin gene is deleted

FUTURE THERAPIES

Resaerching therapeutic agents to stimulate bone formation in patients with osteoporosis.

Excess sclerostin leads to bone loss and bone strength is reduced.

Antibody attaching to sclerostin increases bone formation.

An anti-sclerostin antibody increases BMD in hip and the spine in healthy men and postmenopausal women

SUMMARY

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