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Osteoclast-secreted SLIT3 coordinates bone resorption and formation
Open accessAbstract
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.
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“The formation of H vessels is supported by the production of the slit homolog 3 (SLIT3) protein in osteoclasts,131 which also enhances H vessel branching.131–133”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [131]
In the citing paper
“Osteoclast-derived SLIT3 stimulates the migration and proliferation of osteoblast lineage cells via the activation of β-catenin and suppresses osteoclastogenesis in an autocrine manner.131”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [131]
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Metadata
- Authors
- Kim, B.-J., Lee, Y.-S., Lee, S.-Y., Baek, W.-Y., Choi, Y. J., Moon, S. A., Lee, S. H., Kim, J.-E., Chang, E.-J., Kim, E.-Y., Yoon, J., Kim, S.-W., Ryu, S. H., Lee, S.-K., Lorenzo, J. A., Ahn, S. H., Kim, H., Lee, K.-U., Kim, G. S., & Koh, J.-M.
- Affiliations
- Asan Medical Center (KR)
- University of Connecticut (US)
- Kyungpook National University (KR)
- University of Ulsan (KR)
- Pohang University of Science and Technology (KR)
- UConn Health (US)
- Inha University (KR)
- Corresponding author
- Koh, Jung-Min
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-03-05
- Volume
- 128
- Issue
- 4
- Pages
- 1429-1441
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5873876
- OpenAlex
- W2792461570
- Cited by
- 174
- References
- 52
- Citations by year
- 2026: 23 · 2025: 17 · 2024: 21 · 2023: 27 · 2022: 18 · 2021: 24 · 2020: 26 · 2019: 12 · 2018: 6
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- The Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2258, HI13C1634)
- Asan Institute for Life Sciences, Seoul, Republic of Korea (2015-347)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Bone and Dental Protein Studies
- Keywords
- SLIT3, osteoclasts, bone remodeling, bone resorption, bone formation, coupling coefficient, osteoblast migration, osteoblast proliferation, β-catenin signaling, osteoclastogenesis, osteopenia, ovariectomy, postmenopausal bone loss, metabolic bone disease, axon guidance molecules, secretome
- MeSH terms
- Roundabout Proteins, Animals, Bone Diseases, Metabolic, Bone Resorption, Cell Differentiation, Female, Humans, Male, Membrane Proteins, Nerve Tissue Proteins, Osteoblasts, Osteoclasts, Osteogenesis, Receptors, Immunologic, Mice, Knockout, Autocrine Communication, Mice
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