Nell-1 regulates fibrocartilage stem cells and alleviates temporomandibular joint osteoarthritis progression by inhibiting hedgehog pathway.

Shiyu Hu, Na Wu, Cunyi Wang, Wen Li, Jiejun Shi

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Article in Journal of orthopaedic surgery and research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 authors.

Shiyu Hu *Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China.

Na Wu *Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China.

Cunyi WangDepartment of Stomatology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China.

Wen LiStomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China. ewen74@zju.edu.cn.

Jiejun ShiStomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China. sjiejun@zju.edu.cn.

Funding

National Natural Science Foundation of China 82170984National Natural Science Foundation of China 82471004National Traditional Chinese Medicine Comprehensive Reform Demonstration Zone Science and Technology Cooperation Project GZY-KJS-ZJ-2025-094

6 · The paper itself

Abstract

backgroundNel-like molecule-1 (Nell-1) could prevent the damage of cartilage in osteoarthritis (OA), including temporomandibular joint osteoarthritis (TMJOA), though, the definite mechanism of the process is unclear. Fibrocartilage stem cells (FCSCs) were discovered in the temporomandibular joint (TMJ), and were associated with the TMJ health and disease. However, little information is available on the effect of Nell-1 on FCSCs fate in TMJOA progression.

methodsIn this study, TMJOA was induced in rabbits through collagenase injection. 8 weeks after injection, the left and right joints of the rabbits were injected with AAV9-CMV-Nell-1 and AAV9 vector virus supernatant respectively. FCSCs were isolated, cultured, and transfected with recombinant AdNell-1. Histology staining, immunofluorescence staining, micro-CT, qRT-PCR and western blot were applied to detect the condition of FCSCs and condyles in vitro and in vivo.

resultsIn the collagenase injection group, we observed histological changes consistent with OA, meanwhile, the expression of Nell-1 was decreased, but Indian hedgehog (Ihh) and Sonic hedgehog (Shh) were significantly elevated in FCSCs and condylar cartilage. Further in vitro and in vivo analyses revealed that Nell-1 markedly reduced Ihh and Shh. In addition, Nell-1 induced the chondrogenic differentiation of FCSCs by stimulating the expression of Collagen II, Aggrecan and Sox-9.

conclusionNell-1 leads to improved chondrogenic capacity of FCSCs in TMJOA and demonstrated an inhibitory effect on Hh signal transduction while concurrently facilitating the process of cartilage remodeling. Collectively, Nell-1 may be a promising drug candidate for the treatment of TMJOA.

Indexed as

Calcium-Binding ProteinsFibrocartilageHedgehog ProteinsNerve Tissue ProteinsOsteoarthritisSignal TransductionStem CellsTemporomandibular JointTemporomandibular Joint DisordersAnimalsCells, CulturedDisease ProgressionMaleRabbitsCalcium-Binding ProteinsHedgehog ProteinsNerve Tissue ProteinsCartilageChondrogenic differentiationHedgehogNel-like molecule-1OsteoarthritisTemporomandibular disorders

Identifiers

PMID41535869

DOI10.1186/s13018-025-06461-0

PMCPMC12801752

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LicenceCC BY-NC-ND

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.