Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
J Cell Physiol. 2019 Dec;234(12):23033-23042. doi: 10.1002/jcp.28863. Epub 2019 May 24.
Bone-resorbing osteoclasts are differentiated from macrophages (MΦ) by M-CSF and RANKL. MΦ can be mainly classified into M1 and M2 MΦ, which are proinflammatory and anti-inflammatory, respectively, but little is known about their osteoclastogenic potential. Here, we investigated the osteoclastogenic potential of MΦ subtypes. When the two MΦ subtypes were differentiated into osteoclasts using M-CSF and RANKL, M2 MΦ more potently differentiated into osteoclasts than M1 MΦ. M2 MΦ generated with IL-4 or IL-10 also showed enhanced osteoclast differentiation compared with M1 MΦ induced by IFN-γ and lipopolysaccharide. In addition, robust bone-resorptive capacity and giant actin rings, which are features of mature osteoclasts, were observed in M2, but not M1 MΦ, under the osteoclast differentiation condition. Osteoclast differentiation was significantly increased in CD206 M2 MΦ but not in CD86 M1 MΦ. Compared with M1 MΦ, c-Fms and RANK were highly expressed in M2 MΦ. Enhanced osteoclastogenesis of M2 MΦ was mediated through sustained ERK activation, followed by efficient c-Fos and NFATc1 induction. Notably, the osteoclastogenic potential of M1 MΦ converted into M2 MΦ by exposure to M-CSF was higher than that of M2 MΦ converted into M1 MΦ by exposure to GM-CSF. Silencing IRF5, which is responsible for M1 MΦ polarization, increased osteoclast differentiation by enhancing c-Fms expression and activation of ERK, c-Fos, CREB, and NFATc1, which was inhibited by overexpression of IRF5. Collectively, M2 MΦ are suggested to be more efficient osteoclast precursors than M1 MΦ because of the attenuated expression of IRF5.
破骨细胞由巨噬细胞（MΦ）分化而来，分化过程需要巨噬细胞集落刺激因子（M-CSF）和核因子κB 受体活化因子配体（RANKL）的共同作用。MΦ 可主要分为 M1 和 M2 两种亚型，前者具有促炎作用，后者具有抗炎作用，但人们对其破骨细胞生成潜能知之甚少。在这里，我们研究了 MΦ 两种亚型的破骨细胞生成潜能。当使用 M-CSF 和 RANKL 将两种 MΦ 亚型分化为破骨细胞时，M2 MΦ 比 M1 MΦ 更能有效地分化为破骨细胞。与由 IFN-γ 和脂多糖诱导的 M1 MΦ 相比，由 IL-4 或 IL-10 诱导生成的 M2 MΦ 也表现出增强的破骨细胞分化。此外，在破骨细胞分化条件下，仅在 M2 MΦ 中观察到强大的骨吸收能力和成熟破骨细胞的特征性巨大肌动蛋白环，而在 M1 MΦ 中则没有观察到。在 CD206 M2 MΦ 中，破骨细胞分化明显增加，而在 CD86 M1 MΦ 中则没有。与 M1 MΦ 相比，c-Fms 和 RANK 在 M2 MΦ 中高度表达。M2 MΦ 的破骨细胞生成增强是通过持续的 ERK 激活介导的，随后是有效的 c-Fos 和 NFATc1 诱导。值得注意的是，与由 GM-CSF 诱导的 M2 MΦ 转化为 M1 MΦ 相比，由 M-CSF 诱导的 M1 MΦ 转化为 M2 MΦ 的破骨细胞生成潜能更高。沉默负责 M1 MΦ 极化的干扰素调节因子 5（IRF5）通过增强 c-Fms 表达和 ERK、c-Fos、CREB 和 NFATc1 的激活来增加破骨细胞分化，而 IRF5 的过表达则抑制了这种作用。总的来说，由于 IRF5 表达下调，M2 MΦ 被认为是比 M1 MΦ 更有效的破骨细胞前体细胞。
