TY - JOUR
T1 - Myeloma–bone interaction
T2 - A vicious cycle via tak1–pim2 signaling
AU - Harada, Takeshi
AU - Hiasa, Masahiro
AU - Teramachi, Jumpei
AU - Abe, Masahiro
N1 - Funding Information:
Funding: This work was supported in part by the JSPS KAKENHI Grant Numbers 20K17402 to T.H., 17H05104 and 19K22719 to M.H., 17KK0169 to J.T., and 18K08329 to M.A.; the Japanese Society of Hematology Research Grant (20214 to T.H. and 20247 to J.T.); and the Research Clusters program of Tokushima University (1803003) (M.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
Conflicts of Interest: M.A. received research funding from Chugai Pharmaceutical, Sanofi K.K., Pfizer Seiyaku K.K., Kyowa Hakko Kirin, MSD K.K., Astellas Pharma, Takeda Pharmaceutical, Teijin Pharma and Ono Pharmaceutical, and honoraria from Daiichi Sankyo Company. The other authors declare no competing financial interests.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bonedestructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM.
AB - Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bonedestructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM.
KW - Bone microenvironment
KW - Bone remodeling
KW - Multiple myeloma
KW - PIM2
KW - TAK1
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U2 - 10.3390/cancers13174441
DO - 10.3390/cancers13174441
M3 - Review article
AN - SCOPUS:85114237836
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 17
M1 - 4441
ER -