{
  "abstract": "Oculodentodigital dysplasia (ODDD) is caused by variants in GJA1, but its downstream molecular network remains unclear. This study found that GJA1 defects lead to comprehensive suppression of Wnt/β-catenin signaling and the co-activator c-MYC in patients’ skin fibroblasts and mesenchymal stem cells (MSCs). This change induces a dual pathological process: On the one hand, the loss of Wnt lifts the transcriptional repression of MMP3, leading to abnormally high secretion of matrix metalloproteinases; on the other hand, the absence of c-MYC results in a specific inflammatory bias in NF-κB activation (a surge in IL-6, while CXCL8 (IL-8)are paradoxically and significantly reduced), accompanied by impaired cell migration, proliferation, and osteogenic differentiation. To validate the causal relationship, we demonstrated through genetic intervention that knocking down GJA1 in normal cells replicates the patient phenotype, while overexpressing wild-type GJA1 completely reverses the aforementioned abnormalities. Pharmacological intervention further revealed the hierarchical relationships within the pathway: the Wnt activator (CHIR99021) targets a core upstream hub, correcting CXCL8 abnormalities, inhibiting MMP3, and promoting osteogenesis by restoring c-MYC; in contrast, simply blocking IL-6 (IL6i) acts only on downstream effects; although it can downregulate the interferon response, it fails to restore c-MYC and thus cannot rescue CXCL8 or effectively inhibit MMP3; the combination of the two produces the optimal combined effect. Collectively, we define a novel pathogenic framework linking GJA1 dysfunction to Wnt/c-MYC suppression-driven inflammatory bias and ECM degradation, identifying Wnt activation as a potential therapeutic avenue requiring further validation.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Rare Diseases, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College , ,",
    "Key Laboratory in Science and Technology Development Project of Suzhou (CN), Pediatric Orthopedics, Children’s Hospital of Soochow University , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Siyuan Tao"
    },
    {
      "affs": [
        0
      ],
      "name": "Binshan Zhao"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaodong Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaofang Shen"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiuli Zhao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0j8na7444fxfj.bib",
  "cited_by": 0,
  "doi": "10.3389/fcell.2026.1959966",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719575/?tool=EBI",
  "id": "0j8na7444fxfj",
  "issns": [
    "2296-634X"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13719575",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "1312|Connexins and lens biology"
    ]
  ],
  "openalex": "W7222539978",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719575/pdf/?tool=EBI",
  "pmcid": "PMC13719575",
  "pmid": "42964379",
  "published": "2026-10-16",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/0j8na7444fxfj.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:37Z",
      "native_id": "PMC:PMC13719575",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13719575"
    },
    {
      "first_seen": "2026-11-02T12:23:31Z",
      "native_id": "PMC13719575",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fcell.2026.1959966"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Connexins and lens biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "GJA1 dysfunction suppresses Wnt/c-MYC signaling and promotes inflammatory imbalance and MMP3-associated ECM remodeling in fibroblasts and mesenchymal stromal cells from patients with ODDD",
  "title_text": "GJA1 dysfunction suppresses Wnt/c-MYC signaling and promotes inflammatory imbalance and MMP3-associated ECM remodeling in fibroblasts and mesenchymal stromal cells from patients with ODDD",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:37Z",
  "url": "https://research.draconitic.com/paper/0j8na7444fxfj",
  "venue": "Frontiers in cell and developmental biology",
  "versions": []
}