Objectives Circadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions. Methods RNA was extracted from normal and OA-affected human knee cartilage (n=14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the TGF-β pathway. Results NR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-β signaling pathway. Conclusions The circadian rhythm pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-β signaling, which is a central pathway in cartilage homeostasis.

The T2 value changes reflected histologic tendon healing. While T2 and Bonar grade were lower at all time points in tendons treated with PRP, there was no significant difference between the treatment and control tendons.

IAI-HA prevented gait disturbances in the DMM model, but did not prevent histological changes associated with OA progression.

Matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) are thought to play critical roles in cartilage degradation at the early phase of osteoarthritis (OA). The aim of this study is to examine the effect of chemically modified Mmp13 or Adamts5 small interfering RNA (siRNA), alone or in combination, in a mouse OA model. OA pathology was surgically induced in 9-week-old male C57/BL6 mice (n = 64) via destabilization of the medial meniscus (DMM). We used chemically modified siRNA (Accell siRNAs®) for Mmp13 and Adamts5, as well as a non-targeting control and evaluated their combined and individual effects after injection in the DMM model. The control group (n = 16) was injected with non-targeting siRNA and the normal group (n = 16) did not undergo any surgical induction or intra-articular injection. Histological assessment of the articular cartilage was conducted at 4 and 8 weeks post-DMM surgery to evaluate OA progression. Significant improvement in the histological score was observed at 8 weeks after DMM in all three siRNA-treated groups compared to the control siRNA-injected group. The score of the combined group was significantly lower than that of the Adamts5 siRNA-only group. No significant differences were noted between the Mmp13 siRNA-only group and the combined group. Combined intra-articular injection of Mmp13 and Adamts5 siRNA resulted in almost the same inhibitory effects as Mmp13 siRNA alone on cartilage degradation at the early phase of OA.