Elevated fibrotic markers in patients' synovial fluid correlate significantly with disease stage and inflammation levels.
ARDE injection demonstrated substantial improvements in pain and mouth opening limitation in TMJOA patients.
Radiographic evidence showed reduced joint effusion in some patients following ARDE treatment.
In a rabbit TMJOA model, ARDE facilitated histological cartilage repair and extracellular matrix redeposition.
Co-culture with adipose-derived stem cells suppressed fibrotic marker expression and reduced cellular senescence in chondrocyte models.
ARDE's preparation meets clinical requirements and shows promising safety and efficacy for potential clinical use.
Simplified
BACKGROUND: (TMJOA) is a degenerative joint disease causing chronic pain and restricted mandibular movement. Its complex pathology and lack of effective therapies make it a clinical challenge. Recent studies have demonstrated that cartilage fibrosis correlates closely with TMJOA progression. Inflammatory microenvironments induce chondrocyte senescence, altering secretory phenotypes and driving fibrocartilage formation, characterized by hardened texture and poor mechanical properties, compromising joint biomechanics. Targeting cartilage fibrosis represents a key therapeutic strategy. Stem cell therapies show antifibrotic potential but face clinical limitations due to complex preparation and safety risks.
METHODS: Synovial lavage fluid from TMJOA patients was collected and analyzed for fibrosis marker ACTA2 and inflammatory factor IL-1β expression to confirm intra-articular fibrosis and explore contributing factors. Adipose-derived mesenchymal stem cell (ADSC)-enriched adipose extract (ARDE) was prepared using mechanical emulsification with low-speed centrifugation. Its efficacy was assessed in a prospective clinical trial evaluating pain, mouth opening, and radiographic changes. ARDE's modulation of inflammation and repair of fibrocartilage were histologically assessed in a rabbit TMJOA model. In vitro TMJOA chondrocyte models induced by inflammatory factors (IL-1β, TNF-α) were co-cultured with ARDE's core component, , to observe their impact on pathological chondrocytes. Transcriptome sequencing further explored their repair mechanisms.
RESULTS: TMJOA patient synovial lavage fluid showed elevated fibrotic markers correlating significantly with disease stage and inflammation levels. Prospective clinical trial follow-up demonstrated that ARDE injection substantially improved pain, mouth opening limitation, and quality of life, with reduced joint effusion radiographically evident in some patients. In vivo, intra-articular ARDE promoted histological cartilage repair and extracellular matrix redeposition while downregulating inflammatory factors and fibrotic markers in articular cartilage. Mechanistically, inflammatory cytokine-stimulated chondrocyte models exhibited upregulated fibrotic and senescence-associated pathways; ADSC co-culture suppressed fibrotic marker expression and attenuated cellular senescence.
CONCLUSION: ARDE effectively alleviates cartilage fibrosis by suppressing chondrocyte senescence, significantly restoring cartilage structure and alleviating disease symptoms. The preparation process meets clinical requirements, and its demonstrated safety and efficacy indicate promising clinical translation prospects.
TRIAL REGISTRATION: Human studies were approved by the Medical Ethics Committee of The Third Affiliated Hospital of Air Force Medical University (Approval No: IRB-YJ-2022033) and were registered with the Chinese Clinical Trial Registry (Registration No: ChiCTR2300069677, registered 23 March 2023, https://www.chictr.org.cn/showproj.html?proj=184860 ).
Key numbers
1.8
Pain Score Reduction
score decreased from 5.2 ± 0.7 preoperatively to 1.8 ± 0.3 at one month postoperation.
3.3 cm
Improvement in Mouth Opening
increased from 2.2 ± 0.6 cm preoperatively to 3.3 ± 0.5 cm at one month postoperation.
132.5 ± 15.3 μm
Cartilage Fibrosis Thickness Reduction
thickness in -treated groups was significantly lower than controls at 4 weeks.
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Declarations. Ethics approval and consent to participate: This study adhered to the principles of the Declaration of Helsinki (1975) for medical research involving human subjects. The human studies were approved by the Medical Ethics Committee of The Third Affiliated Hospital of Air Force Medical University (Approval No: IRB-YJ-2022033) and were registered with the Chinese Clinical Trial Registry (Registration No: ChiCTR2300069677). The animal experimental protocols were approved by the Ethics Committee for the Management of Laboratory Animals, School of Stomatology, Air Force Military Medical University (Approval No. kq-2022-082). Consent for publication: All human studies were conducted with informed consent from the participants and their families. All authors agreed on the manuscript. Competing Interests: The authors have no competing interests to declare.
