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

Tobias Braun1, Johannes Lepper, Gisela Ruiz Heiland

  • 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Germany.

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
|November 22, 2012
PubMed

Insights

Mitogen-activated protein kinase 2 (MK2) deficiency impairs osteoclast activity, reducing bone resorption. MK2 knockout mice are protected from age-related bone loss and postmenopausal bone loss, suggesting MK2 inhibitors could treat osteoporosis.

Area of Science:

  • Bone Biology and Endocrinology
  • Molecular Mechanisms of Bone Homeostasis
  • Kinase Signaling in Skeletal Health

Background:

  • Bone homeostasis is a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts.
  • Dysregulation of this balance, particularly increased bone resorption, contributes to conditions like postmenopausal osteoporosis.
  • The serine-threonine kinase mitogen-activated protein kinase 2 (MK2) has been implicated in cellular signaling pathways, but its specific role in bone biology remains to be fully elucidated.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein kinase 2 (MK2) in regulating bone homeostasis.
  • To determine the impact of MK2 deficiency on osteoclast and osteoblast differentiation, function, and gene expression.
  • To evaluate the effect of MK2 on age-related bone loss and bone loss induced by ovariectomy.

Main Methods:

  • Primary bone cell cultures from MK2(+/+) and MK2(-/-) mice were used to assess osteoclast and osteoblast differentiation and bone resorption.
  • Gene expression analysis was performed on osteoclasts.
  • In vivo studies involved micro-computed tomography and histomorphometry to analyze bone architecture in MK2(+/+) and MK2(-/-) mice, with and without ovariectomy.

Main Results:

  • MK2 deficiency significantly impaired osteoclastogenesis, bone resorption, and osteoclast gene expression.
  • Loss of MK2 led to impaired DNA binding of transcription factors c-fos and NFATc1 to key gene promoters involved in osteoclast differentiation.
  • MK2(-/-) mice exhibited increased trabecular bone mass, cortical thickness, and reduced bone resorption markers with age, and were protected from ovariectomy-induced bone loss.
  • Osteoblastogenesis and bone formation were unaffected, but osteoblast expression and serum levels of osteoprotegerin (OPG) were elevated in MK2(-/-) mice.

Conclusions:

  • Loss of MK2 effectively blocks bone resorption by impairing osteoclast differentiation and function.
  • MK2 deficiency prevents ovariectomy-induced bone loss, highlighting its critical role in postmenopausal bone loss.
  • Small-molecule inhibitors targeting MK2 represent a promising therapeutic strategy for blocking bone resorption and treating postmenopausal bone loss.

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