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Targeting osteoblastic Mig6-EGFR signaling ameliorates osteoarthritis progression via inhibiting aberrant subchondral bone remodeling

ABSTRACT: Aberrant subchondral bone remodeling is a critical factor in osteoarthritis (OA) pathogenesis. We observed significant downregulation of Mitogen-induced gene-6 (Mig6) and upregulation of EGFR phosphorylation in subchondral bone osteoblasts, strongly correlating with OA severity in human and animal models. Mig6 is the most important factor mediating mechanical stress-activated EGFR, which inhibits osteogenic activity and modulates mechano-responsiveness. Osteoblast-specific Mig6 deletion exacerbated OA progression by promoting subchondral bone remodeling, whereas gefitinib-mediated inhibition of EGFR phosphorylation attenuated OA symptoms in mice, rats, and Mig6 knockout rats. Furthermore, loss of osteoblastic Mig6 disrupted the subchondral bone microenvironment, increasing inflammation, angiogenesis, and neuronal activity. Mechanistically, aberrant mechanical loading downregulated Mig6, activating phosphorylation of EGFR and the downstream JAK-STAT3 pathway, thereby promoting subchondral bone remodeling and accelerating OA progression. These findings reveal a novel mechanism by which osteoblastic Mig6 regulates subchondral bone remodeling in OA, highlighting Mig6 as a potential therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE302025 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:Osteoarthritis (OA) is a complex degenerative joint disease, which is not only a cartilage but also a bone disease. A better understanding of the early molecular mechanism changes of subchondral bone in vivo may contribute to elucidating the pathogenesis of OA. We used microarray technology to investigate the time-course molecular changes of subchondral bone just beneath damaged cartilage in early stage of experimental osteoarthritis, and found 2,234 differentially expressed (DE) genes at 1 week, 1,944 at 2 weeks and 1,517 at 4 weeks postsurgery.Further analysis of dysregulated genes indicated that subchondral bone remodeling occurred sequentially and in a time-dependent manner at the gene expression level. Some known dysregulated genes suspected roles in influencing bone development or bone remodeling, such as Alp, Igf1, Tgf M-NM-21, Postn, Mmp3, Tnfsf11, Acp5, Bmp5, Aspn and Ihh, were confirmed by real-time PCR, and results indicated that our microarray data could accurately reflect gene expression patterns of early OA. Subsequently, to validate the results of our microarray analysis at protein level, immunohistochemistry staining was introduced to investigate the translational level of genes Mmp3 and Aspn in tissue sections, and results showed that the level of Mmp3 protein expression was totally matched the results of microarray and real-time PCR analysis. Nevertheless, the expression of Aspn protein was not observed differentially expressed at any time point. Ninety 10-week-old male Sprague-Dawley rats, weighing 300-325g, were used in the study. Animals were equally divided into two groups: experimental group (E-Group) and sham-operated group (S-Group). The E-Group rats underwent open surgery, involved in both medial meniscectomy and medial collateral ligament (MCL) transaction with micro-scissors. The S-Group rats were carried out with a sham operation, via a similar incision, without operations of the medial meniscus and the medial collateral ligament.Animals were killed at 1, 2, and 4 weeks postsurgery, and 15 animals were put into use per-timepoint in each treatment group. 5 animals were used for histological analysis and immunohistochemistry, and others were used for microarray study and Real-time polymerase chain reaction (PCR) analysis equally at each timepoint.

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Targeting osteoblastic Mig6-EGFR signaling ameliorates osteoarthritis progression via inhibiting aberrant subchondral bone remodeling

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