Identification of cell cycle-arrested quiescent osteoclast precursors in vivo.

Osteoclasts are multinucleated cells that resorb bone. Although osteoclasts originate from the monocyte/macrophage lineage, osteoclast precursors are not well characterized in vivo. The relationship between proliferation and differentiation of osteoclast precursors is examined in this study using murine macrophage cultures treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB (RANK) ligand (RANKL). Cell cycle–arrested quiescent osteoclast precursors (QuOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments show that QuOPs survive for several weeks and differentiate into osteoclasts in response to M-CSF and RANKL. Administration of 5-fluorouracil to mice induces myelosuppression, but QuOPs survive and differentiate into osteoclasts in response to an active vitamin D3 analogue given to those mice. Mononuclear cells expressing c-Fms and RANK but not Ki67 are detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. These results suggest that QuOPs preexist at the site of osteoclastogenesis and that osteoblasts are important for maintenance of QuOPs.

破骨细胞是吸收骨的多核细胞。尽管破骨细胞起源于单核细胞/巨噬细胞谱系，但破骨细胞前体在体内尚未得到很好的表征。本研究利用经巨噬细胞集落刺激因子（M - CSF）和核因子κB受体激活剂（RANK）配体（RANKL）处理的小鼠巨噬细胞培养物，研究了破骨细胞前体增殖与分化之间的关系。细胞周期停滞的静止破骨细胞前体（QuOPs）在体外被鉴定为定向破骨细胞前体。体内实验表明，QuOPs可存活数周，并在M - CSF和RANKL的作用下分化为破骨细胞。给小鼠施用5 - 氟尿嘧啶会诱导骨髓抑制，但QuOPs在给予活性维生素D3类似物的情况下能够存活并分化为破骨细胞。在RANKL缺陷小鼠中，在成骨细胞附近的骨表面检测到表达c - Fms和RANK但不表达Ki67的单核细胞。这些结果表明，QuOPs预先存在于破骨细胞生成部位，并且成骨细胞对于QuOPs的维持很重要。