Sema 3A plays a protective role in breast cancer-induced osteoclastogenesis and osteolysis

Bone metastasis is the most common complication in patients with solid tumors. Osteoclastogenesis and bone resorption contribute to the pathophysiology of osteoblastic bone metastasis, likewise with osteolytic bone metastasis types. Semaphorin 3A (Sema 3A) has been shown to inhibit RANKL-induced immunoreceptor tyrosinebased activation motif signaling and osteoclastic differentiation, as well as promoting osteogenesis. We previously demonstrated that Sema 3A derived from osteoblastic bone metastasis MCF-7 breast cancer cells stimulates osteoblastic differentiation. In this study, MCF-7 cells were shown to stimulate osteoclastic differentiation in vitro. The stimulation of osteoclastogenesis and bone resorption in RAW264.7 cells and primary mouse bone marrow-derived macrophages by MCF-7 cells was furthermore shown to be enhanced by Sema 3A shRNA or a Sema 3A-neutralizing antibody. The downregulation of Sema 3A expression in MCF-7 cells further promoted p-PLCγ2 expression in RAW264.7 cells. Our findings highlight the importance of Sema 3A as a bidirectional regulatory factor in osteoblastic metastasis: Sema 3A plays a protective role in breast cancer-induced osteoclastogenesis and osteolysis. Targeting Sema 3A for the treatment of osteoblastic metastasis, however, would require precise control and extensive further research.