Zhang H, Wu C, Matesic LE, Li X, Wang Z, Boyce BF, Xing L

Itch is an ubiquitin E3 ligase that regulates protein stability. Itch-/- mice develop an autoimmune disease phenotype characterized by Itchy skin and multi-organ inflammation. However, the role of Itch in the regulation of osteoclast function has not been examined. We report that Itch-/- bone marrow and spleen cells formed more ...

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osteoclasts than cells from WT littermates in response to RANKL, associated with increased expression of the osteoclastogenic transcription factors, c-fos and nfatc1. Over-expression of Itch in Itch-/- cells rescued the exaggerated formation of osteoclasts. Itch-/- osteoclasts had prolonged RANKL-induced NF-kB activation, but a similar degree of RANKL-induced TRAF6 ubiquitination as WT osteoclasts. TRAF6 ubiquitination disappeared after RANKL withdrawal in WT cells, while it persisted in Itch-/- osteoclasts. Itch bound to TRAF6 and to the de-ubiquitinating enzyme, and in the absence of Itch, cylindromatosis (CYLD) in osteoclasts and CYLD binding to TRAF6 was reduced. RANKL increased Itch expression in osteoclasts. The itch promoter contains NF-kB binding sites. Over-expression of NF-kB p65 increased Itch expression and RANKL promoted the binding of p65 onto the NF-kB binding sites in the itch promoter. Three-month-old Itch-/- mice had normal bone volume, but they had significantly increased LPS-induced osteoclastogenesis and bone resorption. Our findings suggest that Itch is a new RANKL target gene, which is induced during osteoclastogenesis. Itch binding to the de-ubiquitin enzyme is required for de-ubiquitination of TRAF6, thus limiting RANKL-induced osteoclast formation.

Date: Jun. 19, 2013

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