title: 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.
authors.affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Braun
authors.forename: Johannes
authors.initials: J
authors.lastname: Lepper
authors.forename: Gisela
authors.initials: G
authors.lastname: Ruiz Heiland
authors.forename: Willy
authors.initials: W
authors.lastname: Hofstetter
authors.forename: Mark
authors.initials: M
authors.lastname: Siegrist
authors.forename: Patrick
authors.initials: P
authors.lastname: Lezuo
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Monika
authors.initials: M
authors.lastname: Rumpler
authors.forename: Roman
authors.initials: R
authors.lastname: Thaler
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption / Q000473:pathology; D002452:Cell Count; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000172:deficiency / Q000378:metabolism*; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D053244:Osteoprotegerin / Q000378:metabolism; D010052:Ovariectomy
chemical_list: D004967:Estrogens; D053244:Osteoprotegerin; D019950:Mitogen-Activated Protein Kinase 1