p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction.
p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction.
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DOI：
10.1158/0008-5472.can-12-2664
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
He J;Liu Z;Zheng Y;Qian J;Li H;Lu Y;Xu J;Hong B;Zhang M;Lin P;Cai Z;Orlowski RZ;Kwak LW;Yi Q;Yang J
在人类骨髓瘤中组成性激活的p38 MAPK与骨髓瘤的骨破坏有关，但其招募的过程尚不清楚。在这项研究中，我们证明了骨髓瘤中的p38活性抑制成骨细胞分化和骨形成，但也促进破骨细胞成熟和骨吸收。p38调节Wnt通路拮抗剂DKK-1和单核细胞趋化剂MCP-1的表达和分泌。减弱p38、DKK-1或MCP-1均足以减少体内骨病变。虽然DKK-1抑制成骨细胞分化是众所周知的，但我们发现它与MCP-1一起也能促进破骨细胞分化和骨吸收。后一种作用是通过增强破骨细胞祖细胞中RANK的表达和上调基质细胞和成熟成骨细胞中RANK配体RANKL的分泌来介导的。总之，我们的研究明确了骨髓瘤细胞中p38信号调控成骨细胞发生、破骨细胞发生和骨破坏的机制。我们的研究结果可能对p38升高的其他癌症的骨侵袭有影响，强烈表明靶向p38抑制可能为治疗骨髓瘤患者的溶骨性骨病变提供有效的治疗方法。
p38 MAPK which is constitutively activated in human myeloma has been implicated in bone destruction by this cancer, but the processes it recruits are obscure. In this study, we demonstrate that p38 activity in myeloma inhibits osteoblast differentiation and bone formation but also enhances osteoclast maturation and bone resorption. p38 regulated the expression and secretion of the Wnt pathway antagonist DKK-1 and the monocyte chemoattractant MCP-1. Attenuating p38, DKK-1 or MCP-1 were each sufficient to reduce bone lesions in vivo. Although it is well known that DKK-1 inhibits osteoblast differentiation, we found that together with MCP-1 it could also promote osteoclast differentiation and bone resorption. The latter effects were mediated by enhancing expression of RANK in osteoclast progenitor cells and by upregulating secretion of its ligand RANKL from stromal cells and mature osteoblasts. In summary, our study defined the mechanisms by which p38 signaling in myeloma cells regulates osteoblastogenesis, osteoclastogenesis, and bone destruction. Our findings, which may have implications for bone invasion by other cancers where p38 is elevated, strongly suggests that targeting p38 for inhibition might offer an effective therapeutic approach to treat osteolytic bone lesions in myeloma patients.