Yu Xuefeng, Huang Yuefang, Collin-Osdoby Patricia, Osdoby Philip
Department of Biology, Washington University, St Louis, Missouri 63130, USA.
J Bone Miner Res. 2003 Aug;18(8):1404-18. doi: 10.1359/jbmr.2003.18.8.1404.
Signals targeting OCs to bone and resorption sites are not well characterized. A chemoattractant receptor (CXCR4), highly expressed in murine OC precursors, mediated their chemokine (SDF-1)-induced chemoattraction, collagen transmigration, and MMP-9 expression. Thus, bone vascular and stromal SDF-1 may direct OC precursors into bone and marrow sites for development and bone resorption.
Although chemokines are essential for trafficking and homing of circulating hematopoietic cells under normal and pathological conditions, their potential roles in osteoclast (OC) recruitment or function are generally unknown. CXCR4 and its unique ligand, stromal cell-derived factor-1 (SDF-1), critically control the matrix metalloproteinase (MMP)-dependent targeting of hematopoietic cells into bone and within the marrow microenvironment. Therefore, SDF-1/CXCR4 may regulate OC precursor recruitment to sites for development and activation.
Chemokine receptor mRNA expression was analyzed during OC formation induced by RANKL in murine RAW 264.7 cells. SDF-1 versus RANKL effects on chemotaxis, transcollagen migration, MMP-9 expression and activity, OC development, and bone resorption were evaluated in RAW cells or RAW-OCs.
CXCR4 was highly expressed in RAW cells and downregulated during their RANKL development into bone-resorptive RAW-OCs. SDF-1, but not RANKL, elicited RAW cell chemotaxis. Conversely, RANKL, but not SDF-1, promoted RAW-OC development, TRAP activity, cathepsin K expression, and bone pit resorption, and SDF-1 did not modify these RANKL responses. Both SDF-1 and RANKL increased MMP-9, a matrix-degrading enzyme essential for OC precursor migration into developing bone marrow cavities, and increased transcollagen migration of RAW cells in a MMP-dependent manner. SDF-1 also upregulated MMP-9 in various primary murine OC precursor cells. Because RANKL induced a higher, more sustained expression of MMP-9 in RAW cells than did SDF-1, MMP-9 may have an additional role in mature OCs. Consistent with this, MMP-9 upregulation during RANKL-induced RAW-OC development was necessary for initiation of bone pit resorption.
SDF-1, a chemokine highly expressed by bone vascular endothelial and marrow stromal cells, may be a key signal for the selective attraction of circulating OC precursors into bone and their migration within marrow to appropriate perivascular stromal sites for RANKL differentiation into resorptive OCs. Thus, SDF-1 and RANKL likely serve complementary physiological functions, partly mediated through increases in MMP-9, to coordinate stages of OC precursor recruitment, development, and function.
靶向破骨细胞至骨骼和吸收部位的信号尚未得到充分表征。一种趋化因子受体（CXCR4）在小鼠破骨细胞前体中高度表达，介导其趋化因子（SDF-1）诱导的化学吸引、胶原迁移和MMP-9表达。因此，骨血管和基质中的SDF-1可能将破骨细胞前体引导至骨骼和骨髓部位进行发育和骨吸收。
尽管趋化因子在正常和病理条件下对循环造血细胞的运输和归巢至关重要，但其在破骨细胞（OC）募集或功能中的潜在作用通常尚不清楚。CXCR4及其独特配体基质细胞衍生因子-1（SDF-1）严格控制造血细胞依赖基质金属蛋白酶（MMP）靶向进入骨骼和骨髓微环境。因此，SDF-1/CXCR4可能调节破骨细胞前体募集至发育和激活部位。
在小鼠RAW 264.7细胞中，分析RANKL诱导破骨细胞形成过程中趋化因子受体mRNA表达。在RAW细胞或RAW破骨细胞中评估SDF-1与RANKL对趋化性、跨胶原迁移、MMP-9表达和活性、破骨细胞发育和骨吸收的影响。
CXCR4在RAW细胞中高度表达，并在其RANKL诱导发育为骨吸收性RAW破骨细胞过程中下调。SDF-1而非RANKL引起RAW细胞趋化。相反，RANKL而非SDF-1促进RAW破骨细胞发育、TRAP活性、组织蛋白酶K表达和骨陷吸收，且SDF-1不改变这些RANKL反应。SDF-1和RANKL均增加MMP-9，MMP-9是破骨细胞前体迁移至发育中的骨髓腔所必需的基质降解酶，并以MMP依赖方式增加RAW细胞的跨胶原迁移。SDF-1还上调各种原代小鼠破骨细胞前体细胞中的MMP-9。由于RANKL在RAW细胞中诱导的MMP-9表达比SDF-1更高、更持久，MMP-9可能在成熟破骨细胞中具有额外作用。与此一致，RANKL诱导RAW破骨细胞发育过程中MMP-9上调是骨陷吸收起始所必需的。
SDF-1是一种由骨血管内皮细胞和骨髓基质细胞高度表达的趋化因子，可能是将循环破骨细胞前体选择性吸引至骨骼并使其在骨髓内迁移至合适的血管周围基质部位以分化为吸收性破骨细胞的关键信号。因此，SDF-1和RANKL可能发挥互补的生理功能，部分通过增加MMP-9介导，以协调破骨细胞前体募集、发育和功能的各个阶段。
