Journal Article

Osteoclast-secreted SLIT3 coordinates bone resorption and formation

Kim, Eun-Young, Ahn, Seong Hee, Kim, Hyeonmok, Koh, Jung-Min, Kim, Seung-Whan, Ryu, Sung Ho, Lee, Ki-Up, Lee, Sun-Kyeong, Kim, Jung-Eun, Moon, Sung Ah, Kim, Ghi Su, Lee, Young-Sun, Lee, Sun-Young, Lee, Seung Hun, Choi, Young Jin, Chang, Eun-Ju, Kim, Beom-Jun, Lorenzo, Joseph A., Yoon, Jin, Baek, Wook-Young

2018

Overview

Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Autocrine Communication / Autocrine signalling / Binding sites / Biomedical research / Bone diseases / Bone Diseases, Metabolic - genetics / Bone Diseases, Metabolic - metabolism / Bone Diseases, Metabolic - pathology / Bone growth / Bone loss / Bone marrow / Bone mass / Bone resorption / Bone Resorption - genetics / Bone Resorption - metabolism / Bone Resorption - pathology / Bone turnover / Cell adhesion molecules / Cell Differentiation / Collagen / Coupling factors / Female / Health aspects / Humans / Male / Medical research / Membrane Proteins - genetics / Membrane Proteins - metabolism / Metabolism / Mice / Mice, Knockout / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Osteoblasts - metabolism / Osteoblasts - pathology / Osteoclastogenesis / Osteoclasts / Osteoclasts - metabolism / Osteoclasts - pathology / Osteogenesis / Osteoporosis / Ovariectomy / Phenotypes / Physiological aspects / Post-menopause / Proteins / Receptors, Immunologic - genetics / Receptors, Immunologic - metabolism / Roles / Roundabout Proteins / Therapeutic applications