CXCL2 attenuates osteoblast differentiation by inhibiting the ERK1/2 signaling pathway
CXCL2 attenuates osteoblast differentiation by inhibiting the ERK1/2 signaling pathway
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CXCL2 通过抑制 ERK1/2 信号通路减弱成骨细胞分化
DOI：
10.1242/jcs.230490
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发表时间：
2019-08-01
影响因子：
4
通讯作者：
Jin, Dadi
中科院分区：
文献类型：
--
作者：
Yang, Yang;Zhou, Xinying;Jin, Dadi
C-X-C基序趋化因子配体2 （CXCL2）是CXC受体配体家族的一员，参与多种免疫和炎症过程，但其对骨形成的影响尚未报道。我们在此报道了CXCL2在骨髓中富集，并在骨质疏松小鼠的成骨细胞中大量表达CXCL2。利用抗体在骨髓内中和CXCL2可减轻小鼠骨丢失，表明CXCL2在骨形成中的负作用。与此相一致的是，CXCL2过表达会减弱体外成骨细胞的增殖和分化。而CXCL2下调则促进成骨细胞的扩张和分化。在机制上，CXCL2抑制成骨细胞的ERK1/2 （MAPK3/1）信号通路。ERK1/2的激活消除了CXCL2在成骨细胞中的抑制作用，而ERK1/2的失活逆转了CXCL2抑制的成骨作用。这些结果表明，CXCL2通过抑制ERK1/2信号通路来减弱成骨细胞的分化。我们在这里证明了CXCL2是骨形成的负调节因子，并阐明了其机制。因此，CXCL2的药物协调及其在成骨细胞中调节的途径可能对骨形成有益。炎性趋化因子CXCL2在骨质疏松的发病机制中发挥重要作用，并通过ERK1/2信号通路抑制成骨细胞分化，从而减缓成骨过程。
ABSTRACT The C-X-C motif chemokine ligand 2 (CXCL2), a member of the CXC receptor ligand family, is involved in various immune and inflammatory processes, but its effect(s) on bone formation have not yet been reported. We report here that CXCL2 is enriched in bone marrow and show abundant expression of CXCL2 in osteoblasts of osteoporotic mice. CXCL2 neutralization within the bone marrow by using antibody alleviated bone loss in mice, indicating a negative role of CXCL2 in bone formation. In line with this, CXCL2 overexpression attenuated proliferation, as well as differentiation, of osteoblasts in vitro. By contrast, CXCL2 downregulation promoted osteoblast expansion and differentiation. Mechanistically, CXCL2 inhibits the ERK1/2 (MAPK3/1) signaling pathway in osteoblasts. Activation of ERK1/2 abolishes the inhibitory effect of CXCL2 in osteoblasts, whereas inactivation of ERK1/2 reverses the osteogenic role of CXCL2 inhibition. These results show that CXCL2 attenuates osteoblast differentiation through inhibition of the ERK1/2 signaling pathway. We demonstrate here that CXCL2 is a negative regulator of bone formation and clarify the responsible mechanisms. Therefore, pharmaceutical coordination of CXCL2 and of the pathways through which it is regulated in osteoblasts might be beneficial regarding bone formation. Highlighted Article: The inflammatory chemokine CXCL2 has an important role in the pathogenesis of osteoporosis and attenuates osteogenesis by inhibiting differentiation of osteoblasts through ERK1/2 signaling.