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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

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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 3

Regulation of bone resorption by SLIT3.

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Regulation of bone resorption by SLIT3.
(A) Histomorphometric analyses i...
(A) Histomorphometric analyses including calcein double labeling of the femur of 7-week-old male Slit3–/– mice and WT littermates (n = 4–5 per group). BFR/BS, bone formation rate per bone surface; MAR, mineral apposition rate; N.Ob/BS, osteoblast number/bone surface; ES/BS, eroded surface/bone surface; OC/BS, multinucleated osteoclast number/bone surface. Scale bars: 10 μm. (B) Serum bone turnover markers in 7-week-old male Slit3–/– mice and WT littermates (n = 9–10 per group). (C) TRAP staining of mouse BMMs with 15 ng/ml M-CSF and 15 ng/ml RANKL for 4 days. (D) The same methods were performed in BMMs obtained from 6-week-old male or female Slit3–/– mice and WT littermates (n = 3 per group). (E) Semiquantitative RT-PCR of Trap, Ctr, and Dc-stamp in mouse BMMs with M-CSF and RANKL. (F) TRAP staining of mouse BMMs with M-CSF and RANKL for 2–3 days. The nuclei number per TRAP-positive cell was counted. (G) Intrabone marrow mobilization of red fluorescent protein–labeled (RFP-labeled) BMMs (n = 5 per group). (H) Western blot of RhoA, Rac, and Cdc42 following 1.0 μg/ml SLIT3 treatment for 15 minutes in mouse BMMs with M-CSF and RANKL. (I) Western blot of Rac GTPase after transfection with empty vector (pCMV5) or mutationally activated Rac1 (Rac1-V12) in mouse BMMs. TRAP staining was also performed at 4 days after transfection. (J) Directional migration of mouse BMMs with 1.0 μg/ml SLIT3 for 24 hours after transfection. Detailed information is supplied in the Supplemental Methods. Data are presented as mean ± SEM. In vitro experiments were performed 3–4 times independently. *P < 0.05 vs. untreated or empty vector–transfected control or between indicated groups using the Mann-Whitney U test or Kruskal-Wallis test followed by Bonferroni’s correction.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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