Mitogen‐activated protein kinase 2 regulates physiological and pathological bone turnover

The objective of this study was to investigate the role of the serine‐threonine kinase mitogen‐activated protein kinase 2 (MK2) in bone homeostasis. Primary bone cell cultures from MK2^+/+ and MK2^–/– mice were assessed for osteoclast and osteoblast differentiation, bone resorption, and gene expression. Bone architecture of MK2^+/+ and MK2^–/– mice was investigated by micro–computed tomography and histomorphometry. Ovariectomy was performed in MK2^+/+ and MK2^–/– mice to assess the role of MK2 in postmenopausal bone loss. Osteoclastogenesis, bone resorption, and osteoclast gene expression were significantly impaired in monocytes from MK2^–/– compared to MK2^+/+ mice. Mechanistically, loss of MK2 causes impaired DNA binding of c‐fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) to tartrate‐resistant acid phosphatase (TRAP) and the calcitonin receptor gene promoter. In addition, MK2^–/– mice showed an age‐dependent increase in trabecular bone mass and cortical thickness, fewer osteoclasts, and lower markers of bone resorption than MK2^+/+ mice. Furthermore, MK2^–/– mice were protected from ovariectomy‐induced bone loss. Osteoblastogenesis and bone formation were unchanged in MK2^–/– mice, whereas osteoblast expression of osteoprotegerin (OPG) and serum levels of OPG were higher in MK2^–/– than in MK2^+/+ mice. Loss of MK2 effectively blocks bone resorption and prevents the development of postmenopausal bone loss. Small‐molecule inhibitors of MK2 could thus emerge as highly effective tools to block bone resorption and to treat postmenopausal bone loss. © 2013 American Society for Bone and Mineral Research.