CONICET | Buscador de Institutos y Recursos Humanos

The contribution of remodeling-based bone formation (BF) coupled to osteoclast activity and modeling-based BF that occurs independently of resorption, to the anabolic effect of PTH remains unclear. Earlier work demonstrated that transgenic (TG) mice with constitutive activation of PTH receptor signaling in osteocytes (DMP1-caPTHR1 mice) display increased endosteal remodeling and enhanced periosteal BF. We dissected herein the contribution of resorption to formation induced by PTHR signaling in osteocytes by administering alendronate (ALN, 5.25 mg/kg/week) or vehicle for 2 weeks to 1-month-old DMP1-caPTHR1, DMP1-Sost, double TG, or wild type (WT) littermates. ALN reduced circulating CTX and OCN in all groups, except for OCN in double TG mice that was already low. The increased periosteal BF displayed by DMP1-caPTHR1 mice was reversed by Sost overexpression but still elevated in DMP1-caPTHR1 mice treated with ALN, demonstrating its dependence on the Wnt pathway but not on resorption.In contrast, the increased endocortical MAR of the DMP1-caPTHR1 mice was abolished by ALN indicating that osteoblast activity in this surface is driven by resorption. Moreover, MAR was further increased by Sost overexpression consistent with the higher resorption and low OPG expression exhibited by these double TG mice. However, the increased endocortical MS/BS displayed by DMP1-caPTHR1 mice was not affected by ALN but it was reduced by Sost overexpression, suggesting that the presence of osteoblasts on mineralizing surfaces induced by PTHR signaling is not driven by resorption but depends on the Wnt pathway. Because of the respective lower values of MAR and MS/BS, double TG mice treated with ALN exhibited endocortical BFR even lower than WT mice, demonstrating cooperation between resorption and Wnt activity on remodeling-based BF driven by PTHR signaling in osteocytes. Moreover, whereas Sost overexpression exacerbated the elevated intra-cortical porosity exhibited by DMP1-caPTHR1 mice, ALN reduced porosity in both DMP1-caPTHR1 and double TG mice. As a result of these combined effects on periosteal and endosteal (endo- and intra-cortical) surfaces, double TG mice treated with ALN exhibited similar bone area in the femoral mid-diaphysis (micro-CT) and femoral BMD (DXA) to WT mice. These findings demonstrate that, although dispensable for periosteal BF, resorption is essential for increasing BF in the endosteal surfaces driven by PTH receptor signaling in osteocytes.

enviar mensaje