Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using Lrp3^−/− mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

Osteoarthritis (OA) is characterized by progressive cartilage degeneration with increasing prevalence and unsatisfactory treatment efficacy. Exosomes derived from mesenchymal stem cells play an important role in alleviating OA by promoting cartilage regeneration, inhibiting synovial inflammation and mediating subchondral bone remodeling without the risk of immune rejection and tumorigenesis. However, low yield, weak activity, inefficient targeting ability and unpredictable side effects of natural exosomes have limited their clinical application. At present, various approaches have been applied in exosome engineering to regulate their production and function, such as pretreatment of parental cells, drug loading, genetic engineering and surface modification. Biomaterials have also been proved to facilitate efficient delivery of exosomes and enhance treatment effectiveness. Here, we summarize the current understanding of the biogenesis, isolation and characterization of natural exosomes, and focus on the large-scale production and preparation of engineered exosomes, as well as their therapeutic potential in OA, thus providing novel insights into exploring advanced MSC-derived exosome-based cell-free therapy for the treatment of OA.

Meniscus is a complex and crucial fibrocartilaginous tissue within the knee joint. Meniscal regeneration remains to be a scientific and translational challenge. We clarified that mesenchymal stem cells (MSCs) participated in meniscal maturation and regeneration using MSC-tracing transgenic mice model. Here, inspired by meniscal natural maturational and regenerative process, we developed an effective and translational strategy to facilitate meniscal regeneration by three-dimensionally printing biomimetic meniscal scaffold combining autologous synovium transplant, which contained abundant intrinsic MSCs. We verified that this facilitated anisotropic meniscus–like tissue regeneration and protected cartilage from degeneration in large animal model. Mechanistically, the biomechanics and matrix stiffness up-regulated Piezo1 expression, facilitating concerted activation of calcineurin and NFATc1, further activated YAP-pSmad2/3-SOX9 axis, and consequently facilitated fibrochondrogenesis of MSCs during meniscal regeneration. In addition, Piezo1 induced by biomechanics and matrix stiffness up-regulated collagen cross-link enzyme expression, which catalyzed collagen cross-link and thereby enhanced mechanical properties of regenerated tissue.

Fibroblast growth factor 18 (FGF18) emerges as a promising therapeutic target for osteoarthritis (OA). In this study, a novel articular cavity‐localized lipid nanoparticle (LNP) named WG‐PL14 is developed. This optimized formulation has a nearly 30‐fold increase in mRNA expression as well as better articular cavity enrichment compared to commercial lipids MC3 when performing intra‐articular injection. Then, a mRNA sequence encoding recombinant human FGF18 (rhFGF18) for potential mRNA therapy in OA is optimized. In vitro assays confirm the translation of rhFGF18 mRNA into functional proteins within rat and human chondrocytes, promoting cell proliferation and extracellular matrix (ECM) synthesis. Subsequently, the therapeutic efficacy of the LNP‐rhFGF18 mRNA complex is systematically assessed in a mouse OA model. The administration exhibits several positive outcomes, including an improved pain response, upregulation of ECM‐related genes (e.g., AGRN and HAS2), and remodeling of subchondral bone homeostasis compared to a control group. Taken together, these findings underscore the potential of localized LNP‐rhFGF18 mRNA therapy in promoting the regeneration of cartilage tissue and mitigating the progression of OA.

Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance