Mechanically Driven Counter-Regulation of Cortical Bone Formation in Response to Sclerostin-Neutralizing Antibodies.
Maude GerbaixPatrick AmmannSerge Livio FerrariPublished in: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2020)
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. © 2020 American Society for Bone and Mineral Research (ASBMR).
Keyphrases
- bone mineral density
- gene expression
- cell proliferation
- soft tissue
- wild type
- bone loss
- bone regeneration
- signaling pathway
- magnetic resonance
- dna methylation
- body composition
- magnetic resonance imaging
- type diabetes
- immune response
- computed tomography
- escherichia coli
- oxidative stress
- blood brain barrier
- insulin resistance
- combination therapy
- zika virus
- cerebral ischemia
- heat stress
- high speed