Metformin, a first-line treatment for type 2 diabetes, attenuates hallmarks of aging and protects against age-related diseases, including osteoarthritis (OA). Here, we assessed the effects of imeglimin, a novel antidiabetic drug synthesized from metformin, on the development and progression of knee OA. Primary human OA chondrocytes, synovial cells, and meniscal cells were stimulated with IL-1β and treated with imeglimin (n = 8). OA-related gene and protein expressions were quantified using RT-qPCR and ELISA. Activation of NF-κB and AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, was assessed using western blotting and immunofluorescence. Additionally, we evaluated its efficacy in two knee OA mouse models (n = 10): destabilization of the medial meniscus and medial collateral ligament transection (DMM+MCLT), and monoiodoacetate (MIA)-induced OA pain. Imeglimin suppressed IL-1β-induced expressions of OA-related genes, including pro-inflammatory (IL6, IL1B, TNF), catabolic (MMP13, ADAMTS5), and pain-related (CCL2, NGF) genes, and reduced IL6 secretion. Western blot analysis revealed downregulation of IκBα and p65 activation and AMPK upregulation. Immunocytochemistry confirmed decreased p65 nuclear translocation (-4245 AU; 95% CI -6765 to -1725). Intra-articular administration of imeglimin reduced histological severity of OA in cartilage, synovium, and meniscus in DMM+MCLT mice (OARSI grade, -3.0 [95% CI: -5.0 to -1.0]), decreased the number of cells expressing p-IκBα in the articular cartilage, and attenuated OA pain in both DMM+MCLT and MIA models. Imeglimin enhances protective functions in joint tissue cells and alleviates experimental OA in preclinical mouse models, supporting its potential as a therapeutic candidate for knee OA.

“Inflammaging” is the presence of continuous systemic low-level chronic inflammation with increasing age, and impairs bone healing. C-C motif chemokine ligand 2 (CCL2) promotes the migration of macrophages during acute inflammation, and subsequent macrophage–mesenchymal stromal cell (MSC) crosstalk. We hypothesized that CCL2 would enhance bone regeneration in both young and aged primary murine cells and investigated the effects of CCL2 on osteogenesis and osteoclastogenesis. In the following experiments, 10–12-week-old and 15–17-month-old female mice were used. For the osteogenic differentiation, MSCs and naïve uncommitted macrophages (M0) were isolated and co-cultured to investigate the effect of CCL2 on the cell–cell interaction, alkaline phosphatase (ALP), and Alizarin-Red staining. For the osteoclastogenic differentiation, primary bone marrow cells were isolated and cultured, then TRAP and Cathepsin K staining and quantitative real-time RT-PCR were performed. In the CCL2-treated group, cells were cultured with recombinant CCL2 for an initial 24 h. MSCs from young mice showed greater osteogenic ability than aged mice. The CCL2-treated group showed a greater Alizarin-Red-positive area both in young and aged cells. In the osteoclastogenic differentiation assays, the number of tartrate-resistant acid phosphatase (TRAP)-positive cells and the expression level of C-fos and Dc-stamp were increased in the CCL2-treated group both in young and aged cells. These findings indicate that CCL2 promotes osteogenesis, particularly mineralization, and enhances selected osteoclastogenic features in both young and aged primary murine cells. These effects suggest that CCL2 may have a potential role in bone remodeling, including in the context of aging.

Complex patient-specific bone defects remain difficult to reconstruct because the regenerative capacity of bone is limited and prefabricated implants cannot readily match defect geometry. In this work, methylcellulose-gelatin-hydroxyapatite (MC/GEL/HA) inks were formulated with varying methylcellulose content and hydroxyapatite incorporation, crosslinked with EDC/NHS, and 3D-printed into porous scaffolds with defined square-pore architectures. Inks were evaluated by oscillatory and steady-shear rheology, and printed scaffolds were characterized for morphology, chemical composition, mechanical performance, physicochemical stability, wettability, apatite-forming bioactivity, and osteogenic responses of human bone marrow mesenchymal stem cells. Methylcellulose content primarily governed ink rheology and printability, and increased compressive strength (up to ~0.38 MPa for 15MC/10GEL/30HA), whereas hydroxyapatite enhanced surface hydrophilicity, promoted apatite nucleation within 7 days in simulated body fluid, and markedly increased alkaline phosphatase activity (>10-fold over HA-free scaffolds), mineralization (~2-fold by Alizarin Red), and the highest osteocalcin expression among the HA-containing formulations (~2.45-fold at day 14). The 15MC/10GEL/30HA formulation showed the most favorable balance of printability, mechanical performance, and osteogenic performance. These complementary functions reconciled structural stability with osteogenic performance, supporting the MC/GEL/HA system as a tunable bioink platform for non-weight-bearing bone regeneration, while warranting further in vivo validation.