Abstract
Simple SummaryMyeloma cells interact with their ambient cells in the bone, such as bone marrow stromal cells, osteoclasts, and osteocytes, resulting in enhancement of osteoclastogenesis and inhibition of osteoblastogenesis while enhancing their growth and drug resistance. The activation of the TAK1–PIM2 signaling axis appears to be vital for this mutual interaction, posing it as an important therapeutic target to suppress tumor expansion and ameliorate bone destruction in multiple myeloma.Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive 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.
Highlights
The skeletal system sustains a body to maintain physical functions
We recently reported that Reveromycin A (RM-A) induced caspase-dependent apoptosis in MM cells at acidic culture conditions but not at pH 7.4 and decreased the progression of a tumor as well as osteolytic lesions in bones in human SCID-rab MM animal models [92]
We recently reported that TGF-β-activated kinase 1 (TAK1) is constitutively overexpressed and phosphorylated in MM cells and that TAK1 acts as an upstream regulator responsible for multiple signaling pathways critical for MM growth and survival, including PIM2-mediated ones (Figure 3) [100]
Summary
The skeletal system sustains a body to maintain physical functions. To maintain the vital roles of bone, bone homeostasis is strictly regulated by the balance between osteoclastic resorption and osteoblastic formation of bone. Osteocytes embedded in the bone matrix are major sensors of mechanical stress to regulate bone remodeling through interaction with bone marrow cells by their dendritic processes [5,6]. Osteocytes regulate both OCs and OBs by elaborating molecules critical for bone metabolism, including RANKL and its inhibitor OPG, and the soluble inhibitors of Wnt/β-catenin signaling pathway sclerostin (SOST) and Dickkopf-1 (DKK-1) [7,8,9]. The direct and indirect crosstalk between osteocytes, OCs, and OBs in the BMU constantly regulates bone remodeling. We will discuss the underlying mechanisms for tumor expansion and bone destruction in MM and approaches to target the MM–bone interaction
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