The role of changes in bone loading driving OA is corroborated by the relationship between weight and pathology in the two models used in this study.
Several computational and in vivo models of bone loading have suggested that loading induces a dynamic flow profile of interstitial fluid through the bone matrix [13] [15].
Metzger, T. A., Schwaner, S. A., LaNeve, A. J., Kreipke, T. C. & Niebur, G. L. Pressure and shear stress in trabecular bone marrow during whole bone loading.
The lack of inflammatory cytokine and morphological changes in 12-week LRLF rat bones indicates that LRLF loading is not high enough to stimulate either bone resorption or formation, as shown in previous studies examining bone loading [ 52, 109, 110].
From this we are confident that in our experiments the (re)modeling response to loading and the changes in gene expression that precede and control it are confined to the bone actually loaded.
To our knowledge, there are few 3D reports that evaluate the load response of bone and joint change in patients with flatfoot deformity, especially in those at stage II PTTD using CT.
One must keep in mind that the mechanisms responsible for bone formation to additional loading and maintaining bone mass with normal load, may not be the same as those for recovering bone mass after unloading39.
In addition to cortical bone, we also measured loading induced changes in trabecular bone, a site more relevant to osteoporotic manifestation.
Many studies have investigated mechanically induced bone formation in mice and rats by applying loads to the long bones, and measuring changes in periosteal cortical bone apposition rates.
To investigate the role of the low-density lipoprotein receptor-related protein 5 (Lrp5) in bones' responses to loading, we analysed changes in multiple measures of bone architecture in tibias subjected to loading or disuse in male and female mice with the Lrp5 loss of function mutation (Lrp5−/−) or heterozygous for the Lrp5 G171V High Bone Mass (HBM) mutation (Lrp5HBM+).
