Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 48, Pages 33343-33351Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.042234
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Funding
- Korea Science and Engineering Foundation [R01-2007-000-11910-0]
- Korea Research Foundation [KRF-2008-314-E00180, KRF-2008-313-E00439]
- Korean Government
- 21C Frontier Functional Proteomics Project [FPR08B1-170]
- Science Research Center [2009-0063269]
- National Research Foundation of Korea [2008-314-E00180, R01-2007-000-11910-0, 2008-313-E00439] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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DYRK1A is a serine/threonine kinase that has been linked to mental retardation associated with Down syndrome. In the present report, we describe a previously unknown role for DYRK1A in bone homeostasis. The protein expression of DYRK1A increased during osteoclast differentiation. In vitro studies in osteoclasts revealed that DYRK1A inhibited osteoclastogenesis. Whereas DYRK1A phosphorylated and inhibited the osteoclastogenic transcription factor NFATc1, forced expression of NFATc1 induced DYRK1A expression, suggesting a negative feedback loop. Transgenic mice overexpressing DYRK1A by the extent of the increased gene dosage in Down syndrome exhibited significantly reduced bone mass despite the decreased osteoclastogenesis, which is reminiscent of osteoporotic bone phenotype in Down syndrome patients. In these mice, attenuated osteoblast differentiation and function in the presence of extra DYRK1A overrode the effect of impaired osteoclastogenesis. However, impeded osteoclastogenesis in DYRK1A transgenic mice was proven to be beneficial in protecting bone loss induced by inflammation or estrogen deficiency. These results provide novel insight into the role for DYRK1A in bone homeostasis as well as in bone destructive diseases, in which modulation of DYRK1A might be used as a strategy to treat unregulated bone resorption.
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