Sclerostin and other cytokine functions in bone.How sclerostin can initiate bone resorption in the body and the mechanisms by which it can do this.

1. SCLEROSTIN
By Irsalan Asif and Shareen Bibi

2. CONTENT
 Structure of Sclerostin
 Mechanism of action
 Regulation of SOST gene/ Sclerostin
 Hormonal regulation
 Potential therapies

3. 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 sclerostin
molecular insight into a key regulator of Wnt-mediated bone formation. Journal of Biological Chemistry. 2009;284(16):10890--10900. Moester
M, 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.

4. 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.

5. MECHANISM OF SCLEROSTIN
ACTION
• Antagonist ofWnt 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.

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

7. MECHANISM OF SCLEROSTIN
ACTION -LPR5/6
 6 bladed propeller unit, the first propeller unit binds to
Sclerostin
 Sclerostin does not compete withWnt 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.

8. 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.

9. 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.

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

11. EFFECT OF AGE ON SCLEROSTIN
• Older age leads to increased Sclerostin levels
• Positive correlation between Sclerostin levels
and age
• May be due to increasedOsteocytes 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.

12. 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.

13. HORMONAL REGULATION
OF SCLOROSTIN

14. Oestrogen
Different types of
hormones that
regulate Sclerostin
Parathyroid hormone
Prostaglandin
E2 and
hypoxia
Glucacorticoi
ds
Calcitonin Cytokins
Zfp467
Ephrin B2
Osterix

15. HOWTHE 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

16.  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

17. 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.

18. 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

19. 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.

20. 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

21. FUTURETHERAPIES
 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

22. SUMMARY

23. THANK YOU