Bone Abstracts

Intermittent PTH administration (iPTH) increases bone mass in humans and animals. PTH exerts its effects by binding to PTH type 1 receptor (PTHR1) predominantly expressed in osteoblasts, resulting in activation of multiple downstream signaling pathways. In vitro investigations have suggested that p38 mitogen-activated protein kinase (MAPK) signaling is an important mediator of PTH-induced osteoblast functions.

To evaluate the contribution of p38alpha MAPK signaling in iPTH-induced bone anabolism, 3-month-old male mice lacking p38α in osteoblasts (Ocn-Cre;p38α^f/f) and their control littermates (p38α^f/f) were treated with daily subcutaneous injections of either 40 μg/kg PTH (1–34) or its vehicle. After 4 weeks of treatment, bone phenotypes were assessed by dexa, microCT, histomorphometry and quantitative gene expression analyses (n=6 per group). Data were analyzed by two-way ANOVA and post hoc analyses were performed using the Holm-Sidak method.

iPTH treatment increased total bone mineral density (+8.5%, P=0.003 vs Veh), femoral cortical thickness (+10.9%, P=0.005), femoral cancellous bone volume (+35.4%, P=0.007) and trabecular thickness (+21.9%, P=0.008) in control mice but did not induce significant changes of those parameters in Ocn-Cre;p38α^f/f mice. Consistent with this, iPTH significantly stimulated trabecular mineralizing surfaces (1.5-fold), mineral apposition rate (1.9-fold) and bone formation rate (2.8-fold) in control animals, whereas it only enhanced mineralizing surfaces (1.5-fold) in Ocn-Cre;p38α^f/f mice, indicating a functional defect of p38α-deficient osteoblasts in response to iPTH. Furthermore, iPTH significantly increased osteoblast marker gene expressions (Col1a1, Alp, BspII and Ocn) in control mice but not in Ocn-Cre;p38α^f/f mice. Finally, p38α-deficient osteoblasts exhibited normal Pthr1 gene expression in comparison to control osteoblasts, but did not display elevations of Alp, BspII and Ocn expressions and matrix mineralization in response to PTH in vitro.

Our findings indicate that the p38α MAPK in osteoblasts plays an important role in PTH-induced bone anabolism in mice.