Unveiling MiR-3085-3p as a modulator of cartilage degeneration in facet joint osteoarthritis: A novel therapeutic target

Abstract

Background: Low back pain (LBP) is generally caused by lumbar degeneration without effective treatment. Lumbar degeneration is influenced by aberrant axial mechanical stress (MS), with facet joint osteoarthritis (FJOA) representing one of its primary pathological manifestations. MicroRNA (miRNA), functioning as an early intermediate in the transcription process, has frequently been demonstrated to serve as a critical mediator linking mechanical stress perception with cellular processes such as growth, development, aging, and apoptosis. We hypothesized that miR-3085-3p regulates chondrocyte apoptosis under mechanical stress, influencing FJOA and serving as a key regulator. Methods: The severity of cartilage degeneration in bipedal standing models (BSM) was established and validated through micro-CT and histopathology. Cyclic tensile strain experiments (CTS) were conducted on the ATDC5 cell line to simulate MS. In situ hybridization was utilized to assess the expression levels of miR-3085-3p in degraded facet articular cartilage. The role of miR-3085-3p and its interaction with the downstream mRNA target Hspb6 were investigated through a combination of bioinformatic analysis, quantitative real-time polymerase chain reaction, western blotting, immunofluorescence, and luciferase assay. In vivo experiments on BSM, the functional impact of miR-3085-3p was further examined through transfection with adeno-associated virus (AAV). Results: It was observed that miR-3085-3p induced endoplasmic reticulum (ER) stress and apoptosis in chondrocytes and cartilage tissues under MS. The detrimental impact of miR-3085-3p was associated with the downregulation of Hspb6 expression, resulting in disruption of endoplasmic reticulum folding function. Additionally, intra-articular transfection of AAV miR-3085-3p mimics in mice facet joints led to spontaneous cartilage loss, while AAV miRNA-3085-3p sponge administration mitigated FJOA in the murine BSM model. Conclusion: Mechanical stress-regulated miR-3085-3p up regulation induced the ER stress and aggravates FJOA development through targeting HSPB6, suggesting miR-3085-3p may be a novel therapeutic target for FJOA.Translational potential of this article: Our study confirmed the elevated expression of miR-3085-3p in lumbar facet joints following mechanical stress loading, suggesting that miR-3085-3p may serve as a biomarker for the clinical management of FJOA. Additionally, we demonstrated that the knockdown of miR-3085-3p in animal facet joints mitigated facet joint degeneration, thereby identifying a potential therapeutic target for FJOA.

Keywords

• Endoplasmic reticulum stress
• Facet joint osteoarthritis
• Mechanical stress
• MiR-3085-3p