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The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

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Abstract

Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38α is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38α in regulating osteoblast function and bone homeostasis, we generated mice lacking p38α in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62 % in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38α showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38α is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

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Acknowledgments

We would like to thank Sabina Troccaz and Pierre Apostolides for their expert technical assistance. We thank Professor Manolis Pasparakis for providing p38a f/f mice and Professor Thomas L. Clemens for Ocn-Cre mice. This work was supported by the Swiss National Science Foundation (310030-127638) and by the Novartis Foundation (Basel, Switzerland).

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The authors state that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Service of Bone Diseases, University Hospital of Geneva, 64 Avenue de la Roseraie, 1205, Geneva, Switzerland

    Cyril Thouverey & Joseph Caverzasio

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  1. Cyril Thouverey
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  2. Joseph Caverzasio
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Correspondence to Joseph Caverzasio.

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The authors declare that the experiments comply with the current laws of Switzerland in which they were performed.

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Thouverey, C., Caverzasio, J. The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition. Cell. Mol. Life Sci. 69, 3115–3125 (2012). https://doi.org/10.1007/s00018-012-0983-8

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  • DOI: https://doi.org/10.1007/s00018-012-0983-8

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