Abstract
Bone adaptation optimizes mass and structure, but the mechano-response is already reduced at maturation. Downregulation of sclerostin was believed to be a mandatory step in mechano-adaptation, but in young mice it was shown that load-induced formation can occur independent of sclerostin, a product of the Sost gene. We hypothesized that the bone formation and resorption response to loading is not affected by Sost deficiency, but is age-specific. Our findings indicate that the anabolic response to in vivo tibial loading was reduced at maturation in Sost Knockout (KO) and littermate control (LC) mice. Age affected all anabolic and catabolic parameters and altered Sost and Wnt target gene expression. While load-induced cortical resorption was similar between genotypes, loading-induced gains in mineralizing surface was enhanced in Sost KO compared to LC mice. Loading led to a downregulation in expression of the Wnt inhibitor Dkk1. Expression of Dkk1 was greater in both control and loaded limbs of Sost KO compared to LC mice suggesting a compensatory role in the absence of Sost. These data suggest physical activity could enhance bone mass concurrently with sclerostin-neutralizing antibodies, but treatment strategies should consider the influence of age on ultimate load-induced bone mass gains.
Highlights
A deficiency in sclerostin, a product of the Sost gene, leads to a high bone mass phenotype in humans and mice[1,2,3]
We hypothesized that the bone formation and resorption response to mechanical loading is not affected by Sost deficiency, but is affected by skeletal maturation
We examined whether two weeks of in vivo tibial loading could enhance bone formation and reduce bone resorption in young and adult female Sost KO and littermate control (LC) mice
Summary
A deficiency in sclerostin, a product of the Sost gene, leads to a high bone mass phenotype in humans and mice[1,2,3]. These regional data suggested that Sost is required for localization of new bone to surfaces experiencing high strains These studies address the question of whether the Wnt inhibitor Sost is required for the anabolic response to loading in young mice, it remains unclear how Wnt signaling is affected during loading under Sost inhibition. Since both these experiments were performed only in young animals it remains unclear if physical activity will be beneficial in terms of increasing bone mass further in adult individuals, which are more prone to suffer from bone loss. No study has yet examined the resorptive response to mechanical loading under sclerostin deficiency, only effects of unloading on resorption in Sost deficient mice have been studied[7]
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