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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Formation of H vessels is supported by production of SLIT3 in osteoclasts, which also enhances H vessel branching.
“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]
Osteoclast-derived SLIT3 stimulates migration and proliferation of osteoblast lineage cells via activation of β-catenin and suppresses osteoclastogenesis in an autocrine manner.
“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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Self-citationPotential Biomarkers to Improve the Prediction of Osteoporotic Fractures
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Self-citationSLIT2 inhibits osteoclastogenesis and bone resorption by suppression of Cdc42 activity
Park, S. J., Lee, J. Y., Lee, S. H., Koh, J., & Kim, B. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.05.046 · Cited by 31 · see citing works
Self-citationMuscle-Derived Lumican Stimulates Bone Formation via Integrin α2β1 and the Downstream ERK Signal
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Self-citationLumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity
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Self-citationRobo2 contains a cryptic binding site for neural EGFL-like (NELL) protein 1/2
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SLIT3 promotes myogenic differentiation as a novel therapeutic factor against muscle loss
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Self-citationKim, B., Lee, J. Y., Park, S. J., Lee, S. H., Kim, S. J., Yoo, H. J., Pena, S. I. R. D., McGee‐Lawrence, M. E., Isales, C. M., Koh, J., et al. (2019) · Aging · doi:10.18632/aging.102389 · Cited by 26 · see citing works
Self-citationNegri, S., Wang, Y., Sono, T., Lee, S., Hsu, G. C., Xu, J., Meyers, C. A., Qin, Q., Broderick, K. P., Witwer, K. W., et al. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.20-0152 · Cited by 26 · see citing works
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Skeletal interoception and prospective application in biomaterials for bone regeneration
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SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling
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Regulation of bone metabolism by megakaryocytes in a paracrine manner
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Self-citationFriend or Foe? Essential Roles of Osteoclast in Maintaining Skeletal Health
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Dehydrocostus lactone (DHC) suppresses estrogen deficiency-induced osteoporosis
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The role of cytokines in bone remodeling and the pathogenesis of postmenopausal osteoporosis
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A Review Into the Insights of the Role of Endothelial Progenitor Cells on Bone Biology
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Osteoclasts drive bone formation in ectopic and orthotopic environments
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Topography-based implants for bone regeneration: Design, biological mechanism, and therapeutics
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An angiogenic approach to osteoanabolic therapy targeting the SHN3-SLIT3 pathway
Yallowitz, A. R., Shim, J., Xu, R., & Greenblatt, M. B. (2023) · Bone · doi:10.1016/j.bone.2023.116761 · Cited by 17 · see citing works
SLIT3 regulates endochondral ossification by β-catenin suppression in chondrocytes
Kim, H., Choi, Y., Lee, Y., Park, S. Y., Baek, J., Kim, H.-K., Kim, B., Lee, S. H., & Koh, J. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.10.167 · Cited by 17 · see citing works
Self-citationBone Cell Communication Factors Provide a New Therapeutic Strategy for Osteoporosis
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Self-citationAnti-osteoporotic potential of Lactobacillus plantarum AR237 and AR495 in ovariectomized mice
Yu, J., Xia, Y., Wang, G., Xiong, Z., Zhang, H., Lai, P. F. H., Song, X., & Ai, L. (2021) · Journal of Functional Foods · doi:10.1016/j.jff.2021.104762 · Cited by 15 · see citing works
Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy
Liu, X., Li, B., Wang, S., Zhang, E., Schultz, M. L., Touma, M., da Rocha, A. M., Evans, S. Μ., Eichmann, A., Herron, T. J., et al. (2024) · Circulation Research · doi:10.1161/circresaha.122.321292 · Cited by 15 · see citing works
Opening windows for bone remodeling through a SLIT
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Self-citationRole of the SLIT-ROBO signaling pathway in renal pathophysiology and various renal diseases
Li, F., Shu, H.-P., Sun, L., Tu, Y.-C., Liao, Q.-Q., & Yao, L. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1226341 · Cited by 14 · see citing works
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C-C motif chemokine ligand 2 promotes myogenesis of myoblasts via the AKT-mTOR pathway
Kwak, M. K., Ha, E. S., Lee, J., Choi, Y. M., Kim, B., & Hong, E. (2022) · Aging · doi:10.18632/aging.204451 · Cited by 12 · see citing works
Self-citationYao, B., Liu, J., Zhang, M., Leng, X., & Zhao, D. (2020) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-020-01677-8 · Cited by 12 · see citing works
Roles of Slit Ligands and Their Roundabout (Robo) Family of Receptors in Bone Remodeling
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SLIT3-mediated fibroblast signaling: a promising target for antifibrotic therapies
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Lee, J. Y., Kim, D. A., Choi, E., Lee, Y. S., Park, S. J., & Kim, B. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.1108 · Cited by 11 · see citing works
Self-citationSLIT2/ROBO1 signaling suppresses mTORC1 for organelle control and bacterial killing
Bhosle, V. K., Tan, J. M. J., Li, T., Hua, R., Kwon, H., Li, Z., Patel, S., Tessier‐Lavigne, M., Robinson, L. A., Kim, P. K., et al. (2023) · Life Science Alliance · doi:10.26508/lsa.202301964 · Cited by 11 · see citing works
The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus
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Gingival crevicular fluid levels of SLIT3 are increased in periodontal disease
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Knockdown of slit signaling during limb development leads to a reduction in humerus length
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Viridicatol from the Deep‐Sea‐Derived Fungus Alleviates Bone Loss by Targeting the Wnt/SHN3 Pathway
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Mesenchymal stem cells in musculoskeletal tissue engineering
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Osteoclast Secretes Stage‐Specific Key Molecules for Modulating Osteoclast–Osteoblast Communication
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Neuronal Guidance Molecules in Bone Remodeling and Orthodontic Tooth Movement
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Effect of CCL11 on In Vitro Myogenesis and Its Clinical Relevance for Sarcopenia in Older Adults
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Messages from the Mineral: How Bone Cells Communicate with Other Tissues
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- 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
- Health Sciences › Medicine › Rheumatology › 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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