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

Abstract

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. Copyright © 2013 American Society for Bone and Mineral Research.