p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction.
p38 mitogen-activated protein kinase (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 show 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 may offer an effective therapeutic approach to treat osteolytic bone lesions in patients with myeloma.
Department of Lymphoma/Myeloma, Division of Cancer Medicine and Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jin
J
He
Zhiqiang
Z
Liu
Yuhuan
Y
Zheng
Jianfei
J
Qian
Haiyan
H
Li
Yong
Y
Lu
Jingda
J
Xu
Bangxing
B
Hong
Mingjun
M
Zhang
Pei
P
Lin
Zhen
Z
Cai
Robert Z
RZ
Orlowski
Larry W
LW
Kwak
Qing
Q
Yi
Jing
J
Yang
D000818:Animals; D001862:Bone Resorption / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases