Kollet Orit, Dar Ayelet, Shivtiel Shoham, Kalinkovich Alexander, Lapid Kfir, Sztainberg Yejezkel, Tesio Melania, Samstein Robert M, Goichberg Polina, Spiegel Asaf, Elson Ari, Lapidot Tsvee
Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Nat Med. 2006 Jun;12(6):657-64. doi: 10.1038/nm1417. Epub 2006 May 21.
Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts (OCLs) along the stem cell-rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9-dependent manner; however, RANKL did not induce mobilization in young female PTPepsilon-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor (SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.
在此，我们研究了破骨细胞在造血祖细胞稳态及应激诱导的动员过程中的潜在作用。不同的应激情况可诱导破骨细胞（OCLs）在富含干细胞的骨内膜区域发挥活性、分泌蛋白水解酶并促使祖细胞动员。用RANKL特异性刺激破骨细胞主要以依赖CXCR4和基质金属蛋白酶-9（MMP-9）的方式将未成熟祖细胞募集到循环中；然而，RANKL在具有缺陷的破骨细胞骨黏附及吸收功能的年轻雌性PTPepsilon基因敲除小鼠中并未诱导动员。用降钙素抑制破骨细胞可减少稳态、粒细胞集落刺激因子（G-CSF）动员及应激情况下祖细胞的外流。RANKL刺激的骨吸收性破骨细胞还可减少骨内膜处的干细胞微环境成分，即基质细胞衍生因子-1（SDF-1）、干细胞因子（SCF）和骨桥蛋白，这与祖细胞动员有关。最后，主要的骨吸收蛋白酶组织蛋白酶K也可裂解SDF-1和SCF。我们的研究结果表明，破骨细胞参与选择性祖细胞募集，作为稳态和宿主防御的一部分，将骨重塑与造血调节联系起来。
