Meniscus plays an important role in joint homeostasis. Tear or degeneration of meniscus might facilitate the process of knee osteoarthritis (OA). Hence, to investigate the transcriptome change during meniscus degeneration, we reveal the alterations of messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) in meniscus during OA by whole-transcriptome sequence. A total of 375 mRNAs, 15 miRNAs, 56 lncRNAs, and 90 circRNAs were significantly altered in the degenerative meniscus treated with interleukin-1β (IL-1β). More importantly, highly specific co-expression RNA (ceRNA) networks regulated by lncRNA LOC107986251-miR-212-5p-SESN3 and hsa_circ_0018069-miR-147b-3p-TJP2 were screened out during IL-induced meniscus degeneration, unveiling potential therapeutic targets for meniscus degeneration during the OA process. Furthermore, lipocalin-2 (LCN2) and RAB27B were identified as potential biomarkers in meniscus degeneration by overlapping three previously constructed databases of OA menisci. LCN2 and RAB27B were both upregulated in osteoarthritic menisci and IL-1β-treated menisci and were highly associated with the severity of OA. This could introduce potential novel molecules into the database of clinical diagnostic biomarkers and possible therapeutic targets for early-stage OA treatment.
AimsThis study aimed to investigate the role and mechanism of meniscal cell lysate (MCL) in fibroblast-like synoviocytes (FLSs) and osteoarthritis (OA).MethodsMeniscus and synovial tissue were collected from 14 patients with and without OA. MCL and FLS proteins were extracted and analyzed by liquid chromatography‒mass spectrometry (LC‒MS). The roles of MCL and adenine nucleotide translocase 3 (ANT3) in FLSs were examined by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, and transmission electron microscopy. Histological analysis was performed to determine ANT3 expression levels in a male mouse model.ResultsWe discovered for the first time that MCL was substantially enriched in the synovial fluid of OA patients and promoted the release of inflammatory cytokines from FLSs through MCL phagocytosis. Through LC‒MS, ANT3 was identified and determined to be significantly upregulated in MCL and OA-FLSs, corresponding to impaired mitochondrial function and cell viability in OA-FLSs. Mitochondrial homeostasis was restored by ANT3 suppression, thereby alleviating synovial inflammation. Furthermore, elevated ANT3 levels inhibited ERK phosphorylation. Specifically, silencing ANT3 prevented inhibition of ERK phosphorylation and significantly reduced the elevation of reactive oxygen species (ROS) and JC1 membrane potential in MCL-induced synovial inflammation.ConclusionThis study revealed the important roles of MCL and ANT3 in FLS mitochondria. Silencing ANT3 rescued ERK phosphorylation, thereby restoring mitochondrial homeostasis in FLSs and alleviating synovitis and OA development, offering a potential target for treating synovitis and preventing early-stage OA.Cite this article: Bone Joint Res 2023;12(4):274–284.
The mechanisms of meniscus fibrosis and novel ways to enhance fibrosis is unclear. This work reveals human meniscus fibrosis initiated at E24 weeks. Smooth muscle cell cluster is identified in embryonic meniscus, and the combined analysis with previous data suggests smooth muscle cell in embryonic meniscus as precursors of progenitor cells in the mature meniscus. NOTCH3 is constantly expressed in smooth muscle cells throughout embryogenesis to adulthood. Inhibition of NOTCH3 signaling in vivo inhibits meniscus fibrosis and exacerbates degeneration. Continuous histological sections show that HEYL, NOTCH3 downstream target gene, is expressed consistently with NOTCH3. HEYL knockdown in meniscus cells attenuated the COL1A1 upregulation by CTGF and TGF-𝜷 stimulation. Thus, this study discovers the existence of smooth muscle cells and fibers in the meniscus. Inhibition of NOTCH3 signaling in meniscus smooth muscle cells in a HEYL-dependent manner prevented meniscus fibrosis and exacerbated degeneration. Therefore, NOTCH3/HEYL signaling might be a potential therapeutic target for meniscus fibrosis.
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