Stromal cell-derived factor-1 binding to its chemokine receptor CXCR4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts
Stromal cell-derived factor-1 binding to its chemokine receptor CXCR4 on precursor cells promotes the chemotactic recruitment, development and survival of human osteoclasts
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DOI：
10.1016/j.bone.2005.01.021
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发表时间：
2005-05-01
期刊：
影响因子：
4.1
通讯作者：
Osdoby, P
中科院分区：
文献类型：
--
作者：
Wright, LM;Maloney, W;Osdoby, P
破骨细胞（Oc）来源于存在于循环和骨髓中的造血前体细胞，并且它们响应于主要由骨髓基质细胞（BMSC）和成骨细胞（Ob）提供的双重必需信号NF-κ B配体受体激活剂（RANKL）和巨噬细胞集落刺激因子（M-CSF）而分化成多核骨吸收细胞。然而，很少有人知道的信号，直接Oc前体从循环到骨或控制它们的迁移在骨髓。基质细胞衍生因子-1（SDF-1或CXCL 12）是一种由骨内皮、BMSC和未成熟Ob高度表达的趋化因子，对于各种造血祖细胞的正常归巢、早期发育和生存至关重要。我们研究了SDF-1及其独特的趋化因子受体CXCR 4是否参与调节人OC前体趋化性、发育、功能或存活。CXCR 4在新鲜分离的人单核细胞（MN）群体、体外产生的OC和OC样细胞以及从人股骨分离的成熟OC中高度表达。与自发迁移细胞相比，SDF-1显著刺激能够产生骨吸收Oc的循环人MN的趋化性募集，导致M-CSF + RANKL诱导分化后Oc形成增加4倍，骨陷窝吸收增加。SDF-1还通过刺激前体细胞数量、多核细胞融合、增加细胞大小和抗酒石酸酸性磷酸酶（TRAP）活性，以与M-CSF + RANKL相似但非加和的方式直接促进Oc发育的早期（而非晚期）阶段。虽然SDF-1不会引起骨吸收Oc的完全发育或直接刺激成熟Oc的吸收功能，但它也不会干扰M-CSF + RANKL促进的任何作用。在成熟的人Oc中，SDF-1被证明与M-CSF + RANKL同样有效地预防由细胞因子撤药诱导的Oc凋亡。在这两种情况下，Oc存活伴随着抗凋亡Bcl-x（L）和Bfl-1相对于促凋亡Bax的mRNA比率的类似升高，以及关键促凋亡信号Bim的显著蛋白抑制。这些发现首次证明SDF-1化学吸引能够发育成骨吸收性Oc的循环人Oc前体，并且它可以刺激MN细胞融合和TRAP活性，在早期破骨细胞生成作用中模拟M-CSF + RANKL，在维持成熟人Oc的存活中替代M-CSF + RANKL，并抑制Bim蛋白的Oc表达。因此，由骨内皮、BMSC和Ob产生的高水平SDF-1可选择性靶向循环Oc前体进入骨，并刺激其骨髓迁移到合适的血管周围基质部位，以促进其早期发育、RANKL分化和存活。因此，SDF-1可能是连接骨血管细胞、BMSC、Ob和Oc在骨发育和重塑的正常稳态调节中的关键因子。(c)2005年爱思唯尔公司All rights reserved.
Osteoclasts (Oc) derive from hematopoietic precursors present in the circulation and bone marrow, and they differentiate into multinucleated bone-resorbing cells in response to the dual essential signals receptor activator of NF-kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) primarily provided by bone marrow stromal cells (BMSC) and osteoblasts (Ob). However, little is known about signals that direct Oc precursors from the circulation into bone or control their migration within the marrow. Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a chemokine highly expressed by bone endothelium, BMSC, and immature Ob that is essential for the normal homing, early development, and survival of various hematopoietic progenitor cells. We investigated whether SDF-1 and its unique chemokine receptor CXCR4 were involved in regulating human Oc precursor chemotaxis, development, function, or survival. CXCR4 was highly expressed by freshly isolated human monocyte (MN) populations, in vitro generated Oc and Oc-like cells, and mature Oc isolated from human femoral bones. SDF-1 markedly stimulated the chemotactic recruitment of circulating human MN capable of generating bone-resorptive Oc, leading to a 4-fold increase in Oc formation and greater bone pit resorption after their M-CSF + RANKL induced differentiation compared to spontaneously migrating cells. SDF-1 also directly promoted early (but not later) stages of Oc development via stimulating precursor cell numbers, multinucleated cell fusion, increased cell size, and tartrate-resistant acid phosphatase (TRAP) activity in a similar, but non-additive, fashion to M-CSF + RANKL. While SDF-1 did not cause full development of bone-resorbing Oc or stimulate the resorptive function of mature Oc directly, it also did not interfere with any actions promoted by M-CSF + RANKL. In mature human Oc, SDF-1 proved equally as effective as M-CSF + RANKL for preventing Oc apoptosis induced by cytokine withdrawal. In both cases, Oc survival was accompanied by analogous rises in the mRNA ratios for anti-apoptotic Bcl-x(L) and Bfl-1 relative to pro-apoptotic Bax, and by marked protein suppression of the critical pro-apoptotic signal Bim. These findings demonstrate for the first time that SDF-1 chemoattracts circulating human Oc precursors capable of developing into bone-resorptive Oc, and that it can stimulate MN cell fusion and TRAP activity, mimic M-CSF + RANKL in early osteoclastogenic effects, substitute for M-CSF + RANKL in maintaining the survival of mature human Oc, and suppress Oc expression of Bim protein. Thus, high levels of SDF-1 produced by bone endothelium, BMSC, and Ob may selectively target circulating Oc precursors into bone and stimulate their marrow migration into suitable perivascular stromal sites for their early development, RANKL differentiation, and survival. Consequently, SDF-1 may be a key factor linking bone vascular cells, BMSC, Ob, and Oc in the normal homeostatic regulation of bone development and remodeling. (c) 2005 Elsevier Inc. All rights reserved.