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The miR4261/PAMM axis in multiple myeloma promotes bone resorption

ABSTRACT: Myeloma bone disease (MBD) affects ~80% of multiple myeloma (MM) patients and remains a major cause of morbidity despite anti-resorptive therapies. Here we identify a previously unrecognized exosome-mediated mechanism by which MM cells directly promote osteoclastogenesis. Tumor-derived exosomal miR-4261 is transferred to monocyte precursors, directly targets and represses PAMM (PRXL2A/FAM213A)—an antioxidant protein that negatively regulates osteoclast differentiation—and thereby accelerates osteoclast formation and bone resorption. In two independent MM cohorts, serum exosomal miR-4261 was significantly elevated in patients with MBD, whereas PAMM expression was reduced; low PAMM strongly correlated with hypercalcaemia. PAMM knockdown recapitulated the pro-osteoclastogenic effects of miR-4261, and RNA-seq/GSEA revealed selective downregulation of negative regulators of osteoclast differentiation (including TNFAIP6, CCL3, and TLR3). These findings establish the miR-4261/PAMM axis as a novel driver of myeloma-induced bone destruction and suggest serum exosomal miR-4261 as a promising liquid-biopsy biomarker and therapeutic target in MBD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315264 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.

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The miR4261/PAMM axis in multiple myeloma promotes bone resorption

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