Osteoclast-secreted SLIT3 coordinates bone resorption and formation
Beom-Jun Kim, … , Ghi Su Kim, Jung-Min Koh
Beom-Jun Kim, … , Ghi Su Kim, Jung-Min Koh
Published March 5, 2018
Citation Information: J Clin Invest. 2018;128(4):1429-1441. https://doi.org/10.1172/JCI91086.
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Research Article Bone biology Article has an altmetric score of 16

Osteoclast-secreted SLIT3 coordinates bone resorption and formation

Abstract

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.

Authors

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

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Figure 6

Effect of LRRD2 of human SLIT3 on bone mass in OVX mice.

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Effect of LRRD2 of human SLIT3 on bone mass in OVX mice. (A) Directional...
(A) Directional migration of mouse calvaria osteoblasts upon treatment with the same molar concentration of SLIT3 (1.0 μg/ml = 10 nM) and LRRD2 for 24 hours using a Boyden chamber system. The invaded cell numbers were counted. (B) Proliferation of mouse calvaria osteoblasts in the presence of SLIT3 or LRRD2 for 48 hours assessed using a BrdU incorporation assay. (C) TRAP staining of mouse BMMs exposed to 15 ng/ml M-CSF and 15 ng/ml RANKL in the presence of SLIT3 or LRRD2 for 4 days. TRAP-positive cells with more than 3 nuclei were counted. (D) Von Kossa staining and histomorphometric analyses including calcein double-labeling of the femur of sham-operated, OVX, and LRRD2-treated OVX mice (n = 7 per group). The female C57BL/6J mice were OVX at 8 weeks of age, and 2 μg LRRD2 was injected via the tail vein twice a day (mean 0.192 mg/kg/day) from 12 weeks of age for 4 weeks. The same volume of saline was injected in the other groups. Mice were then sacrificed for analyses at 16 weeks of age. Scale bars: 500 μm (left panels); 10 μm (right panels). Data are presented as mean ± SEM. In vitro experiments were performed 3 times independently. *P < 0.05 vs. untreated control or between the indicated groups using the Mann-Whitney U test or Kruskal-Wallis test followed by Bonferroni’s correction. †P < 0.05 vs. 5 nM-treated group using Mann-Whitney U test.