Top

Osteoporosis International

Published in:

Open Access 01-04-2012 | Original Article

Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered

Authors: A. Moustafa, T. Sugiyama, J. Prasad, G. Zaman, T. S. Gross, L. E. Lanyon, J. S. Price

Published in: Osteoporosis International | Issue 4/2012

Abstract

Summary

Osteocyte sclerostin is regulated by loading and disuse in mouse tibiae but is more closely related to subsequent local osteogenesis than the peak strains engendered.

Introduction

The purpose of this study was to assess the relationship between loading-related change in osteocyte sclerostin expression, local strain magnitude, and local bone modeling/remodeling.

Methods

The right tibiae of 19-week-old female C57BL/6 mice were subjected to non-invasive, dynamic axial loading and/or to sciatic neurectomy-induced disuse. The sclerostin status of osteocytes was evaluated immunohistochemically, changes in bone mass by micro-computed tomography, new bone formation by histomorphometry, and loading-induced strain by strain gauges and finite element analysis.

Results

In cortical bone of the tibial shaft, loading engendered strains of similar peak magnitude proximally and distally. Proximally, sclerostin-positive osteocytes decreased and new bone formation increased. Distally, there was neither decrease in sclerostin-positive osteocytes nor increased osteogenesis. In trabecular bone of the proximal secondary spongiosa, loading decreased sclerostin-positive osteocytes and increased bone volume. Neither occurred in the primary spongiosa. Disuse increased sclerostin-positive osteocytes and decreased bone volume at all four sites. Loading reversed this sclerostin upregulation to a level below baseline in the proximal cortex and secondary spongiosa.

Conclusion

Loading-related sclerostin downregulation in osteocytes of the mouse tibia is associated preferentially with regions where new bone formation is stimulated rather than where high peak strains are engendered. The mechanisms involved remain unclear, but could relate to peak surface strains not accurately reflecting the strain-related osteogenic stimulus or that sclerostin regulation occurs after sufficient signal processing to distinguish between local osteogenic and non-osteogenic responses.

Price JS, Sugiyama T, Galea GL, Meakin LB, Sunters A, Lanyon LE (2011) Role of endocrine and paracrine factors in the adaptation of bone to mechanical loading. Curr Osteoporos Rep 9:76–82PubMedCrossRef

Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276PubMedCrossRef

van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Lowik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814PubMedCrossRef

Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844PubMed

Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K (2007) Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 5:464–475PubMedCrossRef

Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875PubMedCrossRef

Moustafa A, Sugiyama T, Saxon LK, Zaman G, Sunters A, Armstrong VJ, Javaheri B, Lanyon LE, Price JS (2009) The mouse fibula as a suitable bone for the study of functional adaptation to mechanical loading. Bone 44:930–935PubMedCrossRef

Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 24:1651–1661PubMedCrossRef

Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, Ferrari SL (2009) The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem 284:35939–35950PubMedCrossRef

10.

Callewaert F, Bakker A, Schrooten J, Van Meerbeek B, Verhoeven G, Boonen S, Vanderschueren D (2010) Androgen receptor disruption increases the osteogenic response to mechanical loading in male mice. J Bone Miner Res 25:124–131PubMedCrossRef

11.

Zaman G, Saxon LK, Sunters A, Hilton H, Underhill P, Williams D, Price JS, Lanyon LE (2010) Loading-related regulation of gene expression in bone in the contexts of estrogen deficiency, lack of estrogen receptor alpha and disuse. Bone 46:628–642PubMedCrossRef

12.

Ominsky MS, Vlasseros F, Jolette J, Smith SY, Stouch B, Doellgast G, Gong J, Gao Y, Cao J, Graham K, Tipton B, Cai J, Deshpande R, Zhou L, Hale MD, Lightwood DJ, Henry AJ, Popplewell AG, Moore AR, Robinson MK, Lacey DL, Simonet WS, Paszty C (2010) Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 25:948–959PubMedCrossRef

13.

Padhi D, Jang G, Stouch B, Fang L, Posvar E (2011) Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 26:19–26PubMedCrossRef

14.

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887PubMedCrossRef

15.

Semenov M, Tamai K, He X (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775PubMedCrossRef

16.

Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, van Bezooijen RL, Hatsell S, Economides AN, Mueller TD, Lowik CW, ten Dijke P (2010) Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. J Biol Chem 285:41614–41626PubMedCrossRef

17.

Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869PubMedCrossRef

18.

Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543PubMedCrossRef

19.

Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589PubMedCrossRef

20.

Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97PubMedCrossRef

21.

Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P, Papapoulos S, Hamersma H, Brunkow ME (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152PubMedCrossRef

22.

Ralston SH, Uitterlinden AG (2010) Genetics of osteoporosis. Endocr Rev 31:629–662PubMedCrossRef

23.

Power J, Poole KE, van Bezooijen R, Doube M, Caballero-Alias AM, Lowik C, Papapoulos S, Reeve J, Loveridge N (2010) Sclerostin and the regulation of bone formation: effects in hip osteoarthritis and femoral neck fracture. J Bone Miner Res 25:1867–1876PubMedCrossRef

24.

De Souza RL, Matsuura M, Eckstein F, Rawlinson SC, Lanyon LE, Pitsillides AA (2005) Non-invasive axial loading of mouse tibiae increases cortical bone formation and modifies trabecular organization: a new model to study cortical and cancellous compartments in a single loaded element. Bone 37:810–818PubMedCrossRef

25.

Sugiyama T, Price JS, Lanyon LE (2010) Functional adaptation to mechanical loading in both cortical and cancellous bone is controlled locally and is confined to the loaded bones. Bone 46:314–321PubMedCrossRef

26.

Sugiyama T, Galea GL, Lanyon LE, Price JS (2010) Mechanical loading-related bone gain is enhanced by tamoxifen but unaffected by fulvestrant in female mice. Endocrinology 151:5582–5590PubMedCrossRef

27.

Srinivasan S, Weimer DA, Agans SC, Bain SD, Gross TS (2002) Low-magnitude mechanical loading becomes osteogenic when rest is inserted between each load cycle. J Bone Miner Res 17:1613–1620PubMedCrossRef

28.

McKenzie JA, Silva MJ (2011) Comparing histological, vascular and molecular responses associated with woven and lamellar bone formation induced by mechanical loading in the rat ulna. Bone 48:250–258PubMedCrossRef

29.

Prasad J, Wiater BP, Nork SE, Bain SD, Gross TS (2010) Characterizing gait induced normal strains in a murine tibia cortical bone defect model. J Biomech 43:2765–2770PubMedCrossRef

30.

Stadelmann VA, Hocke J, Verhelle J, Forster V, Merlini F, Terrier A, Pioletti DP (2009) 3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements. Comput Methods Biomech Biomed Engin 12:95–100PubMedCrossRef

31.

Lynch ME, Main RP, Xu Q, Walsh DJ, Schaffler MB, Wright TM, van der Meulen MCH (2010) Cancellous bone adaptation to tibial compression is not sex-dependent in growing mice. J Appl Physiol 109:685–691PubMedCrossRef

32.

Vincent C, Findlay DM, Welldon KJ, Wijenayaka AR, Zheng TS, Haynes DR, Fazzalari NL, Evdokiou A, Atkins GJ (2009) Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J Bone Miner Res 24:1434–1449PubMedCrossRef

33.

Heiland GR, Zwerina K, Baum W, Kireva T, Distler JH, Grisanti M, Asuncion F, Li X, Ominsky M, Richards W, Schett G, Zwerina J (2010) Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis 69:2152–2159PubMedCrossRef

34.

Mosley JR, March BM, Lynch J, Lanyon LE (1997) Strain magnitude related changes in whole bone architecture in growing rats. Bone 20:191–198PubMedCrossRef

35.

Gross TS, Edwards JL, McLeod KJ, Rubin CT (1997) Strain gradients correlate with sites of periosteal bone formation. J Bone Miner Res 12:982–988PubMedCrossRef

36.

Nicolella DP, Bonewald LF, Moravits DE, Lankford J (2005) Measurement of microstructural strain in cortical bone. Eur J Morphol 42:23–29PubMedCrossRef

37.

Nicolella DP, Moravits DE, Gale AM, Bonewald LF, Lankford J (2006) Osteocyte lacunae tissue strain in cortical bone. J Biomech 39:1735–1743PubMedCrossRef

38.

Silvestrini G, Ballanti P, Sebastiani M, Leopizzi M, Di Vito M, Bonucci E (2008) OPG and RANKL mRNA and protein expressions in the primary and secondary metaphyseal trabecular bone of PTH-treated rats are independent of that of SOST. J Mol Histol 39:237–242PubMedCrossRef

39.

Yamane H, Sakai A, Mori T, Tanaka S, Moridera K, Nakamura T (2009) The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice. Bone 44:1055–1062PubMedCrossRef

40.

Gross TS, Rubin CT (1995) Uniformity of resorptive bone loss induced by disuse. J Orthop Res 13:708–714PubMedCrossRef

41.

Gaudio A, Pennisi P, Bratengeier C, Torrisi V, Lindner B, Mangiafico RA, Pulvirenti I, Hawa G, Tringali G, Fiore CE (2010) Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 95:2248–2253PubMedCrossRef

42.

Mirza FS, Padhi ID, Raisz LG, Lorenzo JA (2010) Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 95:1991–1997PubMedCrossRef

43.

Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2010) Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 25:178–189PubMedCrossRef

44.

Drake MT, Srinivasan B, Modder UI, Peterson JM, McCready LK, Riggs BL, Dwyer D, Stolina M, Kostenuik P, Khosla S (2010) Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women. J Clin Endocrinol Metab 95:5056–5062PubMedCrossRef

45.

Sugiyama T, Saxon LK, Zaman G, Moustafa A, Sunters A, Price JS, Lanyon LE (2008) Mechanical loading enhances the anabolic effects of intermittent parathyroid hormone (1–34) on trabecular and cortical bone in mice. Bone 43:238–248PubMedCrossRef

Title: Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered
Authors: A. Moustafa
T. Sugiyama
J. Prasad
G. Zaman
T. S. Gross
L. E. Lanyon
J. S. Price
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 4/2012
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-011-1656-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenic response than the peak strains engendered

Abstract

Summary

Introduction

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2012

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

Non-elite gymnastics participation is associated with greater bone strength, muscle size, and function in pre- and early pubertal girls

Prevalence of osteoporosis among cancer patients in Germany

The effects of combined human parathyroid hormone (1-34) and zoledronic acid treatment on fracture healing in osteoporotic rats

Fracture risk assessment in patients with chronic kidney disease

The multiple facets of periostin in bone metabolism