Yao Zhenqiang, Li Yanyun, Yin Xiaoxiang, Dong Yufeng, Xing Lianping, Boyce Brendan F
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA; Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
J Bone Miner Res. 2014 Apr;29(4):866-77. doi: 10.1002/jbmr.2108.
RelA-mediated NF-κB canonical signaling promotes mesenchymal progenitor cell (MPC) proliferation, but inhibits differentiation of mature osteoblasts (OBs) and thus negatively regulates bone formation. Previous studies suggest that NF-κB RelB may also negatively regulate bone formation through noncanonical signaling, but they involved a complex knockout mouse model, and the molecular mechanisms involved were not investigated. Here, we report that RelB(-/-) mice develop age-related increased trabecular bone mass associated with increased bone formation. RelB(-/-) bone marrow stromal cells expanded faster in vitro and have enhanced OB differentiation associated with increased expression of the osteoblastogenic transcription factor, Runt-related transcription factor 2 (Runx2). In addition, RelB directly targeted the Runx2 promoter to inhibit its activation. Importantly, RelB(-/-) bone-derived MPCs formed bone more rapidly than wild-type cells after they were injected into a murine tibial bone defect model. Our findings indicate that RelB negatively regulates bone mass as mice age and limits bone formation in healing bone defects, suggesting that inhibition of RelB could reduce age-related bone loss and enhance bone repair.
RelA介导的核因子κB经典信号通路促进间充质祖细胞（MPC）增殖，但抑制成熟成骨细胞（OB）分化，从而对骨形成产生负调控作用。以往研究表明，核因子κB RelB也可能通过非经典信号通路对骨形成产生负调控作用，但这些研究涉及复杂的基因敲除小鼠模型，且未对其中涉及的分子机制进行研究。在此，我们报道RelB基因敲除小鼠出现与骨形成增加相关的年龄相关性小梁骨量增加。RelB基因敲除小鼠的骨髓基质细胞在体外增殖更快，且与成骨转录因子—— runt相关转录因子2（Runx2）表达增加相关的OB分化增强。此外，RelB直接作用于Runx2启动子以抑制其激活。重要的是，将RelB基因敲除小鼠的骨源性MPC注射到小鼠胫骨骨缺损模型中后，其形成骨的速度比野生型细胞更快。我们的研究结果表明，随着小鼠年龄增长，RelB对骨量产生负调控作用，并限制愈合骨缺损中的骨形成，这表明抑制RelB可减少年龄相关性骨质流失并增强骨修复。
