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Myeloma

Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma

Leukemia volume 26, pages 2114–2123 (2012)Cite this article

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A Corrigendum to this article was published on 04 February 2015

Abstract

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.

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Acknowledgements

We thank Brian Dawson for technical support with ÎĽ-CT scanning and analysis. We also thank our departmental Myeloma Tissue Bank for patient samples. This work was supported by National Cancer Institute R01 Grants CA138402 and CA138398 and P50 Grant CA142509 (Q Yi), the Leukemia and Lymphoma Society Translational Research grants, the Multiple Myeloma Research Foundation (Q Yi), the Commonwealth Foundation for Cancer Research (Q Yi), National Cancer Institute K99/R00 Grant CA137158 (J Yang), the International Myeloma Foundation (J Yang), the Lymphoma Research Foundation (J Yang), the American Society of Hematology (J Yang), and by funds from the University Cancer Foundation and the Center for Targeted Therapy of The University of Texas MD Anderson Cancer Center (Q Yi).

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Authors and Affiliations

  1. Department of Lymphoma/Myeloma, Division of Cancer Medicine, and the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Yang, J He, J Wang, Y Cao, J Qian, Y Lu, H Li, Y Zheng, Y Lan, S Hong, J Matthews, R Z Orlowski, L W Kwak & Q Yi

  2. Department of Surgical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Ling

  3. Department of Genitourinary Medical Oncology - Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M W Starbuck & N M Navone

  4. Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Lin

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Yang, J., He, J., Wang, J. et al. Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma. Leukemia 26, 2114–2123 (2012). https://doi.org/10.1038/leu.2012.71

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