Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma.
Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma.
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骨质破坏是多发性骨髓瘤的标志，影响超过80%的患者。然而，目前的疗法不能完全治愈和/或预防骨病变。虽然骨髓瘤细胞通过抑制成骨细胞和激活破骨细胞介导骨破坏已被公认，但其潜在机制仍知之甚少。本研究表明，骨髓瘤细胞中p38丝裂原活化蛋白激酶的组成性激活是骨髓瘤诱导的骨质溶解的原因。我们的研究结果表明，p38在大多数骨髓瘤细胞系和原发性骨髓瘤细胞的患者组成性激活。具有高/可检测的p38活性的骨髓瘤细胞，但不是那些具有低/不可检测的p38活性的骨髓瘤细胞，注射到SCID或SCID-hu小鼠中引起骨破坏。在人类骨髓瘤中抑制或敲低p38可减少或预防骨髓瘤诱导的溶骨性骨病变，而不影响肿瘤生长、存活或归巢至骨。机制研究表明，骨髓瘤细胞p38活性抑制成骨细胞和骨形成，并激活破骨细胞和骨吸收骨髓瘤荷SCID小鼠。本研究阐明了一种新的分子机制骨髓瘤细胞中p38信号的激活骨髓瘤细胞通过这种机制诱导溶骨性骨病变，并表明靶向骨髓瘤细胞p38可能是治疗或预防骨髓瘤骨病的可行方法。
Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into SCID or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism—sactivation of p38 signaling in myeloma cells—by which myeloma cells induce osteolytic bone lesions and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease.
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影响因子：
4.1
作者：
Suzuki, A;Guicheux, J;Caverzasio, J
通讯作者：
Caverzasio, J
影响因子：
15.3
作者：
Awasthi, A;Mathur, R;Saha, B
通讯作者：
Saha, B
影响因子：
4.8
作者：
Wang, L;Ma, R;Choi, ME
通讯作者：
Choi, ME
DOI：
10.1359/jbmr.090806
发表时间：
2010-02
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Kamiya N;Kobayashi T;Mochida Y;Yu PB;Yamauchi M;Kronenberg HM;Mishina Y
通讯作者：
Mishina Y
影响因子：
6.2
作者：
Guicheux, J;Lemonnier, J;Caverzasio, J
通讯作者：
Caverzasio, J