Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2012 Sep;26(9):2114-23. doi: 10.1038/leu.2012.71. Epub 2012 Mar 19.
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 severe combined immunodeficient (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-activation 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.
骨破坏是多发性骨髓瘤的一个标志，影响超过 80%的患者。然而，目前的治疗方法无法完全治愈和/或预防骨病变。尽管人们普遍认为骨髓瘤细胞通过抑制成骨细胞和激活破骨细胞来介导骨破坏，但潜在的机制仍知之甚少。本研究表明，骨髓瘤细胞中 p38 丝裂原活化蛋白激酶的持续激活是骨髓瘤诱导的溶骨性骨病变的原因。我们的研究结果表明，大多数骨髓瘤细胞系和来自患者的原代骨髓瘤细胞中 p38 持续激活。具有高/可检测的 p38 活性的骨髓瘤细胞，但不具有低/不可检测的 p38 活性的骨髓瘤细胞，注入严重联合免疫缺陷（SCID）或 SCID-hu 小鼠中会引起骨破坏。在人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、存活或归巢到骨。机制研究表明，骨髓瘤细胞 p38 活性抑制成骨细胞生成和骨形成，并激活骨髓瘤荷瘤 SCID 小鼠中的破骨细胞生成和骨吸收。本研究阐明了骨髓瘤细胞中 p38 信号的激活这一新型分子机制，骨髓瘤细胞通过该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一种可行方法。
