Activation of SLIT2/ROBO1/LRP6 axis aggravates cartilage degradation via β-catenin signaling in TMJOA
Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu
Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu
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Research Article Bone biology Inflammation

Activation of SLIT2/ROBO1/LRP6 axis aggravates cartilage degradation via β-catenin signaling in TMJOA

Abstract

Temporomandibular joint osteoarthritis (TMJOA), a prevalent subtype of temporomandibular disorders, is characterized by progressive cartilage degradation and subchondral bone destruction. Despite advancements in understanding TMJOA pathogenesis, the molecular mechanisms underlying its progression remain unclear. In this study, elevated Slit guidance ligand 2 (SLIT2) expression was observed in TMJ tissues of unilateral anterior crossbite–induced TMJOA mice and synovial fluid from patients with TMJOA, correlating with disease severity. Furthermore, SLIT2 overexpression in transgenic mice intensified TMJOA progression, whereas heterozygous deletion of roundabout guidance receptor 1/2 (ROBO1/2) alleviated cartilage and bone damage. Mechanistically, SLIT2 promoted ROBO1-LRP6 complex formation, facilitating LRP6 phosphorylation and β-catenin nuclear translocation. This cascade upregulated matrix-degrading enzymes while downregulating cartilage structural proteins, exacerbating cartilage destruction and subchondral bone loss. These findings suggest that the SLIT2/ROBO1/LRP6 axis may represent a potential therapeutic target for TMJOA and provide mechanistic insights into disease progression.

Authors

Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu

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Figure 4

SLIT2 led to an inflammatory response and catabolism in chondrocytes.

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SLIT2 led to an inflammatory response and catabolism in chondrocytes. (A...
(A) Western blot detection of the effects of SLIT2 overexpression in primary chondrocytes from 3-week-old C57 and SLIT2-Tg mice. Primary chondrocytes for each independent isolation batch were pooled from 3 mice, and the process was repeated 3 times. (B) Relative quantification of COL2A1, MMP13, and IL-1β proteins. (C) qRT-PCR analysis of the effect of SLIT2 overexpression in primary chondrocytes from 3-week-old C57 or SLIT2-Tg mice. (D) Western blot detection of COL2A1, MMP13, and MMP3 after 48 hours of treatment with rhSLIT2 at 0, 10, 20, 50, and 100 ng/mL in SW1353 cells. (E) Relative quantification of COL2A1, MMP3, MMP13 and SOX9 proteins. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with the 0 ng/mL group. (F) Western blot detection of the effect of SLIT2 knockdown on human chondrocytes treated with NC or Si-SLIT2 sequence for 48 hours. (G) Relative quantification of MMP3, MMP13, and SOX9 proteins. (H) qRT-PCR detection of the effect of SLIT2 knockdown on SW1353 cells treated with NC or Si-SLIT2 sequence for 24 hours. (I) A heatmap illustrating differentially expressed genes related to TMJOA from RNA-seq analysis between the NC and Si-SLIT2 groups. (J) GO analysis of 12 key terms from the top terms. All data are shown as mean ± SD. Statistical significance was assessed by 2-tailed Student’s t test (B, C, G, and H) and 1-way ANOVA with Dunnett’s multiple-comparison test (E). *P < 0.05; **P < 0.01; ***P < 0.001.