Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China.
Orthopaedic Institute, Medical College, Soochow University, Suzhou 215007, China.
Oxid Med Cell Longev. 2021 Dec 31;2021:9661200. doi: 10.1155/2021/9661200. eCollection 2021.
A balance between bone formation by osteoblasts and bone resorption by osteoclasts is necessary to maintain bone health and homeostasis. As a cancer of plasma cells, multiple myeloma (MM) is accompanied with rapid bone loss and fragility fracture. Bortezomib has been used as a first-line for treating MM for decades. Recently, the potential protection of bortezomib on osteoporosis (OP) is reported; however, the specific mechanism involving bortezomib-mediated antiosteoporotic effect is undetermined. In the present study, we assessed the effects of bortezomib treatment on osteogenesis and osteoclastogenesis and the protective effect on bone loss in ovariectomized (OVX) mice. Our results indicated that bortezomib treatment increased osteogenic differentiation of MC3T3-E1 cells as evidenced by increased levels of matrix mineralization and osteoblast-specific markers. In bortezomib-treated bone marrow monocytes (BMMs), osteoclast differentiation was suppressed, substantiated by downregulated tartrate-resistant acid phosphatase- (TRAP-) positive multinucleated cells, areas of actin rings, pit formation, and osteoclast-specific genes. Mechanistically, bortezomib exerted a protective effect against OP through the Smad ubiquitination regulatory factor- (SMURF-) mediated ubiquitination pathway. Furthermore, intraperitoneal injection of bortezomib attenuated the bone microarchitecture in OVX mice. Accordingly, our findings corroborated that bortezomib might have future applications in the treatment of postmenopausal OP.
成骨细胞形成骨与破骨细胞吸收骨之间的平衡对于维持骨骼健康和体内平衡是必要的。作为浆细胞瘤的一种，多发性骨髓瘤（MM）伴随着快速的骨质流失和脆性骨折。硼替佐米已被用作治疗 MM 的一线药物数十年。最近，有报道称硼替佐米对骨质疏松症（OP）具有潜在的保护作用；然而，涉及硼替佐米介导的抗骨质疏松作用的具体机制尚不确定。在本研究中，我们评估了硼替佐米治疗对成骨和破骨的影响以及对去卵巢（OVX）小鼠骨丢失的保护作用。我们的结果表明，硼替佐米治疗增加了 MC3T3-E1 细胞的成骨分化，表现为基质矿化和成骨细胞特异性标志物水平增加。在硼替佐米处理的骨髓单核细胞（BMM）中，破骨细胞分化受到抑制，这一点可以通过下调抗酒石酸酸性磷酸酶阳性多核细胞、环状肌动蛋白区、陷窝形成和破骨细胞特异性基因来证实。在机制上，硼替佐米通过 Smad 泛素化调节因子（SMURF）介导的泛素化途径发挥对 OP 的保护作用。此外，腹腔注射硼替佐米可减轻 OVX 小鼠的骨微观结构。因此，我们的研究结果证实，硼替佐米可能在治疗绝经后 OP 方面具有应用前景。
