Regulation of cortical bone formation by SLIT and NTRK-like family member 1
Mutations in SLIT and NTRK-like family member 1 (<i>SLITRK1</i>) result in Tourette syndrome (TS). Patients with TS exhibit delayed bone maturation and increased fracture risk. To understand the role of SLITRK1 in bone homeostasis, we examined the skeletal phenotype of <i>Slitrk1</i> null mice and investigated the mechanisms responsible for altered bone cell function. <i>Slitrk1 null</i> mice had thinner cortical bones due to decreased periosteal bone formation, while trabecular bone density remained unchanged. <i>Slitrk1</i> was expressed within osteoblast-lineage cells. Consequently, deletion of <i>Slitrk1</i> in osteoblasts impaired <i>ex vivo</i> differentiation capacity. Loss of SLITRK1 in osteoblast cells reduced levels of TAZ, a RUNX2 co-activator necessary for osteoblast differentiation. These findings provide evidence for a cell-autonomous role of SLITRK1 in periosteal osteoblasts regulating cortical bone homeostasis. Our data further demonstrate that periosteal-, endosteal-, and trabecular-bone homeostasis are controlled by different mechanisms and provide new insight into the skeletal manifestations of TS.
Authors
- Quan Yuan (ORCID: https://orcid.org/0000-0002-0676-2079)
- Mitsushiro Nakatomi (ORCID: https://orcid.org/0000-0001-8713-210X)
- Kayoko N. Kuroishi
- Kenichi Nagano (ORCID: https://orcid.org/0000-0003-3145-4841)
- Takuma Matsubara (ORCID: https://orcid.org/0000-0002-8505-0431)
- Takumi Ito (ORCID: https://orcid.org/0000-0002-6376-584X)
- William N. Addison (ORCID: https://orcid.org/0000-0002-8587-8028)
- Tsuyoshi Sato (ORCID: https://orcid.org/0000-0002-1109-196X)
- T. Kawamoto (ORCID: https://orcid.org/0000-0002-5841-5511)
- Tomohiko Shirakawa
- Jun Aruga (ORCID: https://orcid.org/0000-0001-7936-1375)
- Shoichiro Kokabu (ORCID: https://orcid.org/0000-0002-6663-4327)
- Chihiro Nakatomi (ORCID: https://orcid.org/0000-0003-2049-6624)
- H. Kaneda (ORCID: https://orcid.org/0009-0001-4008-5577)
- Miho Inoue
- Minoru Hatayama
Institutions
- University of Occupational and Environmental Health Japan (JP)
- Nagasaki Institute of Applied Science (JP)
- Kyushu Dental University (JP)
- Sichuan University (CN)
- Juntendo University (JP)
- Nagasaki University (JP)
- State Key Laboratory of Oral Diseases
Publication Details
- Journal
- iScience
- Published
- 2025-05-30
- DOI
- https://doi.org/10.1016/j.isci.2025.112788
- Primary Topic
- Growth Hormone and Insulin-like Growth Factors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Society for the Promotion of Science