Department of Medicine, Division of Rheumatology, UCSF, San Francisco, California, USA.
J Clin Invest. 2012 Dec;122(12):4592-605. doi: 10.1172/JCI60920. Epub 2012 Nov 1.
Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b(-/lo)Ly6C(hi) BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell-suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.
破骨细胞骨吸收增加导致 RA 患者关节周围侵蚀和全身性骨质疏松症。尽管人们已经了解了破骨细胞如何从前体细胞分化并吸收骨,但体内破骨细胞前体细胞(OCP)群体的身份及其在 RA 中的调节作用仍不清楚。在这里,我们报告了在体外和体内鉴定出具有 OCP 活性的 CD11b(-/lo)Ly6C(hi)BM 群体。这些细胞可与髓系中先前表征的前体细胞区分开来,具有 M1 和 M2 单核细胞的特征,并在炎症性关节炎模型中扩增。令人惊讶的是,在一种 RA 小鼠模型(SKG 关节炎的过继转移)中,与 SKG CD4+T 细胞共转移 OCP 可减少炎症性关节炎。与单核细胞髓系来源的抑制细胞(M-MDSCs)类似,OCP 通过产生 NO 在体外抑制 CD4+和 CD8+T 细胞增殖。这项研究确定了一种具有破骨细胞和 T 细胞抑制活性的 BM 髓样前体细胞群体,该群体在炎症性关节炎中扩增。防止 OCP 发育为成熟的骨吸收细胞的治疗策略可以同时防止骨吸收并在 RA 关节中产生抗炎环境。