In a recent review article published in the journal Cancers, the authors discussed the underlying mechanisms of bone destruction in multiple myeloma (MM) and the potential to therapeutically target the MM-bone interaction to suppress tumor expansion and ameliorate bone destruction.

MM has a propensity to develop in bone and form bone-destructive lesions. MM cells stimulate bone resorption by enhancing osteoclastogenesis through activation of the RANKL-NF-KB signaling pathway and suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs). Factors involved in this process include the soluble Wnt inhibitors DKK-1, sFRP2,3, and sclerostin, TNFα, IL-7, IL-3, activin A, and TGF-β, which cooperatively act and eventually develop bone-destructive lesions in MM.

Recently, osteocytes have drawn attention as multifunctional regulators of bone metabolism. MM cells alter the microenvironments through bone destruction in the bone where they reside, inducing apoptosis in osteocytes. This triggers the production of factors, including RANKL, sclerostin, and DKK-1, which create a cycle that further exacerbates bone destruction and wherein tumor growth and survival are enhanced.


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The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in BMSCs and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1-PIM2 pathway in MM cells and the interaction with the bone marrow environment leads to activation of the JAK2/STAT3 pathway for IL-6 and the NF-KB pathway for TNF family cytokines, TNFα, BAFF, and APRIL, promoting MM cell growth and survival.

The authors argued that because PIM2 is also induced in osteoclasts and BMSCs through the interaction with MM cells, leading to bone destruction, the TAK1-PIM2 pathway of the bone marrow microenvironment appears to be an important therapeutic target.

“[T]he development of new agents to regain bone mass and strengthen muscular function is wanted. Because TAK1 and PIM2-mediated signaling are vital for tumor expansion and bone destruction in MM, the development of novel agents to target TAK1 and/or PIM2 may play a role,” the authors wrote. “Further elucidation of the molecular mechanisms of MM cell and/or MM CSC-bone interactions will provide us with new approaches that have a real impact on both bone disease and tumor progression in MM.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Harada T, Hiasa M, Teramachi J, Abe M. Myeloma-bone interaction: a vicious cycle via TAK1-PIM2 signaling. Cancers (Basel). 2021;13(17):4441. doi:10.3390/cancers13174441