sclerostin edit 2
TRANSCRIPT
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.
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