Bone Abstracts

Selective p38α inhibitors have been found to prevent bone loss induced by estrogen deficiency but implicated mechanisms remained to be identified. The p38 MAPK pathway has been suggested to influence bone resorption at different regulatory levels. In osteoblasts, p38α has been reported to be involved in the production of osteoclastogenic interleukin 6 and Rankl in response to various bone-resorptive agents in vitro. Therefore, we investigated whether p38α in osteoblasts may contribute to ovariectomy-induced bone loss in mice.

Mice lacking p38α in osteoblasts (Ocn-Cre;p38α^f/f) and their control littermates (p38α^f/f) were either sham-operated or ovariectomized at 12 weeks of age. Their bone phenotypes were assessed 6 weeks after operations by dexa, micro-CT, histomorphometry and gene expression analyses (n=7 per group). Data were analyzed by two-way ANOVA and post hoc analyses were performed using the Holm-Sidak method.

Ovariectomy caused a decrease in bone mineral density in the spine (−13.1%; P<0.001 vs sham) and to a lesser extent in the femur (−1.8%; P<0.001 vs sham) of control mice but not in Ocn-Cre;p38α^f/f mice (+12.7% in the spine; +8.1% in the femur; P<0.01 vs p38α^f/f). In addition, ovariectomy decreased vertebral cancellous bone volume (−45.8%; P<0.01 vs sham), trabecular thickness (−16%; P<0.01), and trabecular number (−20.6%; P<0.01) in control mice but not in Ocn-Cre;p38α^f/f mice, indicating that mice lacking p38α in osteoblasts were protected from ovariectomy-induced bone loss. Consistent with this, ovariectomy caused an increase in osteoclast surface (fourfold), osteoclast number (threefold) and serum level of CTX (1.4-fold) in p38α^f/f mice but not in Ocn-Cre;p38α^f/f mice. Finally, ovariectomy induced a twofold increase in interleukin 6 expression in the long bones of p38α^f/f mice (P<0.05), whereas this osteoclastogenic cytokine was downregulated in Ocn-Cre;p38α^f/f mice.

Our findings indicate that the p38α MAPK in osteoblasts contributes to ovariectomy-induced bone loss by upregulating interleukin 6 expression.