Department of Laboratory Sciences, Graduate School of Health Sciences, Gunma University, Maebashi 371-8510, Japan.
Laboratory of Mucosal Ecosystem Design, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8510, Japan.
Int J Mol Sci. 2023 Jan 22;24(3):2216. doi: 10.3390/ijms24032216.
Tissue inhibitors of metalloproteinases (TIMPs) are endogenous matrix metalloproteinase inhibitors. TIMP1 is produced by cancer cells and has pleiotropic activities. However, its role and source in multiple myeloma (MM) are unclear. Here, we evaluated TIMP1 protein and mRNA levels in bone marrow (BM) plasma cells and assessed the effects of TIMP1 expression on fibroblast invasive capacity using three-dimensional spheroid cell invasion assays. mRNA and protein levels were elevated when patients progressed from monoclonal gammopathy of undetermined significance or smouldering myeloma to MM. Furthermore, TIMP1 levels decreased at complete response and TIMP1 protein levels increased with higher international staging. mRNA levels were markedly higher in extramedullary plasmacytoma and MM with t(4;14). Overall survival and post-progression survival were significantly lower in MM patients with high TIMP1 protein. Recombinant TIMP1 did not directly affect MM cells but enhanced the invasive capacity of fibroblasts; this effect was suppressed by treatment with anti-TIMP1 antibodies. Fibroblasts supported myeloma cell invasion and expansion in extracellular matrix. Overall, these results suggested that MM-derived TIMP1 induces the invasive phenotype in fibroblasts and is involved in disease progression. Further studies are required to elucidate the specific roles of TIMP1 in MM and facilitate the development of novel therapies targeting the TIMP1 pathway.
组织金属蛋白酶抑制剂（TIMP）是内源性基质金属蛋白酶抑制剂。TIMP1 由癌细胞产生，具有多种活性。然而，其在多发性骨髓瘤（MM）中的作用和来源尚不清楚。在这里，我们评估了骨髓（BM）浆细胞中 TIMP1 蛋白和 mRNA 水平，并使用三维球体细胞侵袭测定评估了 TIMP1 表达对成纤维细胞侵袭能力的影响。当患者从意义未明的单克隆丙种球蛋白病或冒烟型骨髓瘤进展为 MM 时，mRNA 和蛋白水平升高。此外，在完全缓解时 TIMP1 水平降低，国际分期越高，TIMP1 蛋白水平越高。在伴有 t(4;14)的骨髓外浆细胞瘤和 MM 中，mRNA 水平明显更高。TIMP1 蛋白水平高的 MM 患者的总生存和无进展生存显著降低。重组 TIMP1 不会直接影响 MM 细胞，但可增强成纤维细胞的侵袭能力；用抗 TIMP1 抗体治疗可抑制这种作用。成纤维细胞支持骨髓瘤细胞在细胞外基质中的侵袭和扩增。综上所述，这些结果表明 MM 来源的 TIMP1 诱导成纤维细胞的侵袭表型，并参与疾病进展。需要进一步研究以阐明 TIMP1 在 MM 中的具体作用，并促进针对 TIMP1 途径的新型治疗方法的开发。
