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Scientific article
English

Mechanically Driven Counter‐Regulation of Cortical Bone Formation in Response to Sclerostin‐Neutralizing Antibodies

Published inJournal of Bone and Mineral Research, vol. 36, no. 2, p. 385-399
Publication date2021
Abstract

Sclerostin (Scl) antibodies (Scl-Ab) potently stimulate bone formation, but these effects are transient. Whether the rapid inhibition of Scl-Ab anabolic effects is due to a loss of bone cells' capacity to form new bone or to a mechanostatic downregulation of Wnt signaling once bone strength exceeds stress remains unclear. We hypothesized that bone formation under Scl-Ab could be reactivated by increasing the dose of Scl-Ab and/or by adding mechanical stimuli, and investigated the molecular mechanisms involved in this response, in particular the role of periostin (Postn), a co-activator of the Wnt pathway in bone. For this purpose, C57Bl/6, Postn-/- and Postn+/+ mice were treated with vehicle or Scl-Ab (50 to 100 mg/kg/wk) for various durations and subsequently subjected to tibia axial compressive loading. In wild-type (WT) mice, Scl-Ab anabolic effects peaked between 2 and 4 weeks and declined thereafter, with no further increase in bone volume and strength between 7 and 10 weeks. Doubling the dose of Scl-Ab did not rescue the decline in bone formation. In contrast, mechanical stimulation was able to restore cortical bone formation concomitantly to Scl-Ab treatment at both doses. Several Wnt inhibitors, including Dkk1, Sost, and Twist1, were upregulated, whereas Postn was markedly downregulated by 2 to 4 weeks of Scl-Ab. Mechanical loading specifically upregulated Postn gene expression. In turn, Scl-Ab effects on cortical bone were more rapidly downregulated in Postn-/- mice. These results indicate that bone formation is not exhausted by Scl-Ab but inhibited by a mechanically driven downregulation of Wnt signaling. Hence, increasing mechanical loads restores bone formation on cortical surfaces, in parallel with Postn upregulation.

Keywords
  • Anabolics
  • Bone modeling and remodeling
  • Exercise
  • Sclerostin antibodies
Citation (ISO format)
GERBAIX, Maude Coline, AMMANN, Patrick, FERRARI, Serge Livio. Mechanically Driven Counter‐Regulation of Cortical Bone Formation in Response to Sclerostin‐Neutralizing Antibodies. In: Journal of Bone and Mineral Research, 2021, vol. 36, n° 2, p. 385–399. doi: 10.1002/jbmr.4193
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ISSN of the journal0884-0431
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