Abstract
Carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal (BMS) cells derived from Chip−/− mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip-deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFα-induced NF-κB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-κB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip−/− mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling.
Highlights
Bone remodeling is a dynamic process, involving a balance between the activity of bone-forming osteoblasts, derived from mesenchymal progenitor cells, and the activity of bone-resorbing osteoclasts, derived from hematopoietic stem cells.[1]
The dynamic process of bone remodeling was impaired in Chip−/− mice, suggesting that CHIP plays a critical role in bone remodeling
Our previous study showed that TRAF6 protein levels are increased in Chip-deficient osteoclasts and we have characterized the effect of CHIP on regulation of TRAF6 protein stability.[12]
Summary
Bone remodeling is a dynamic process, involving a balance between the activity of bone-forming osteoblasts, derived from mesenchymal progenitor cells, and the activity of bone-resorbing osteoclasts, derived from hematopoietic stem cells.[1] A disruption of this balance leads to many bone and joint diseases, especially metabolic bone diseases. Osteoclasts are derived from hematopoietic stem cells which undergo proliferation and differentiation to become multinucleated bone-resorbing osteoclasts.[2] The process of osteoclastogenesis is regulated by several cytokines such as RANKL and TNF-α,3 which activate NF-κB signaling.[2] TNF-α receptor-associated factors (TRAFs) are intracellular adapter proteins, which play critical roles in NF-κB signaling.[4,5] In TRAF family members, TRAF2, TRAF5, and TRAF6 have been shown to activate NF-κB signaling.[6] TRAF2 and TRAF5 interact with TNF-α receptors and mediate TNF-α-induced osteoclast formation. We found that in addition to TRAF6, CHIP induced the degradation of TRAF2 and TRAF5, but not TRAF3
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