Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency

Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38 alpha MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38 alpha-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor kappa B ligand and IL-6 expression in mice lacking p38 alpha in osteoblasts and osteocytes. Finally, TNF alpha or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38 alpha signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38 alpha MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor kappa B ligand and IL-6 production.