Gene deletion or treatments with a cathepsin K (CatK) inhibitor in mature preclinical models result not only result in lower bone resorption but also in higher bone formation (BF) on both remodeling and modeling surfaces. Although increased production of clastokines and matrix-derived growth factors may explain the increased BF at remodeling surfaces, the mechanisms for greater BF at modeling surfaces, including the periosteum, remain unexplained. We hypothesized that the absence of the CatK gene (Ctsk) enhances the skeletal response to mechanical loading. To test this hypothesis, in vivo cyclic axial compression (40 cycles, 7 min, 3day/week, for 2 weeks) was applied to the left tibia of 12 weeks old Ctsk−/− mice and their WT littermates (n=6 per groups), while the non-loaded (NL) tibia served as the comparator. Since Ctsk−/− mice have higher bone mass vs WT, the compression force was adjusted to 16N and 12N, respectively, in order to achieve 17001800 microstrain in both types of mice. Loading stimulated tibia BMD gain in Ctsk−/− (+24.2±3.2 vs +0.2±0.3 mg/cm2 in NL) more than that in WT (+9.0±1.4 vs +0.9±1.9 mg/cm2, P<0.01 for genotype x load inter.; P<0.001 Ctsk−/− vs WT). At the tibia midshaft, periosteal (Ps) MAR and BFR, as well as endocortical MAR, MPm/BPm and BFR were all significantly increased by loading in Ctsk−/−, whereas only Ps.MAR was modestly increased in WT (+60% vs 566% in Ctsk−/−, P<0.05). As a result, loading increased cortical bone volume fraction (Ct.BV/TV, +19%) and thickness (CtTh, +35%), in Cstk−/− (both P<0.001), but not in WT. Furthermore, when the same compression force (16N) was applied to both Ctsk−/− and WT mice, i.e. a lower strain in Ctsk−/−, Ps.BFR and CtTh still increased more in Ctsk−/− than WT (+1765% vs +494% and +35% vs +15%, respectively, both P<0.05). In conclusion, deletion of CatK enhances the long bone adaptation to load at both Ec and Ps surfaces. While endocortical BF in Cstk−/− mice may result from increased production of growth factors within the BMUs, the results from this study suggest the presence of novel CatK-related molecular targets at periosteal surfaces.
17 May 2014 - 20 May 2014