The interplay between immune cells/macrophages and fibroblast‐like synoviocytes (FLSs) plays a pivotal role in initiating synovitis; however, their involvement in metabolic disorders, including diabetic osteoarthritis (DOA), is largely unknown. In this study, single‐cell RNA sequencing (scRNA‐seq) is employed to investigate the synovial cell composition of DOA. A significant enrichment of activated macrophages within eight distinct synovial cell clusters is found in DOA synovium. Moreover, it is demonstrated that increased glycolysis in FLSs is a key driver for DOA patients’ synovial macrophage infiltration and polarization. In addition, the yes‐associated protein 1 (YAP1)/thioredoxin‐interacting protein (TXNIP) signaling axis is demonstrated to play a crucial role in regulating glucose transporter 1 (GLUT1)‐dependent glycolysis in FLSs, thereby controlling the expression of a series of adhesion molecules such as intercellular adhesion molecule‐1 (ICAM‐1) which may subsequently fine‐tune the infiltration of M1‐polarized synovial macrophages in DOA patients and db/db diabetic OA mice. For treatment, M1 macrophage membrane‐camouflaged Verteporfin (Vt)‐loaded PLGA nanoparticles (MVPs) are developed to ameliorate DOA progression by regulating the YAP1/TXNIP signaling axis, thus suppressing the synovial glycolysis and the infiltration of M1‐polarized macrophages. The results provide several novel insights into the pathogenesis of DOA and offer a promising treatment approach for DOA.

Soft hydrogels are excellent candidate materials for repairing various tissue defects, yet the mechanical strength, anti-swelling properties, and biocompatibility of many soft hydrogels need to be improved. Herein, inspired by the nanostructure of collagen fibrils, we developed a strategy toward achieving a soft but tough, anti-swelling nanofibrillar hydrogel by combining the self-assembly and chemical crosslinking of nanoparticles. Specifically, the collagen fibril-like injectable hydrogel was subtly designed and fabricated by self-assembling methylacrylyl hydroxypropyl chitosan (HM) with laponite (LAP) to form nanoparticles, followed by the inter-nanoparticle bonding through photo-crosslinking. The assembly mechanism of nanoparticles was elucidated by both experimental and simulation techniques. Due to the unique structure of the crosslinked nanoparticles, the nanocomposite hydrogels exhibited low stiffness (G’< 2 kPa), high compressive strength (709 kPa), and anti-swelling (swelling ratio of 1.07 in PBS) properties. Additionally, by harnessing the photo-crosslinking ability of the nanoparticles, the nanocomposite hydrogels were processed as microgels, which can be three-dimensionally (3D) printed into complex shapes. Furthermore, we demonstrated that these nanocomposite hydrogels are highly biocompatible, biodegradability, and can effectively promote fibroblast migration and accelerate blood vessel formation during wound healing. This work presents a promising approach to develop biomimetic, nanofibrillar soft hydrogels for regenerative medicine applications.

Osteoarthritis (OA) has been recognized as an age-related degenerative disease commonly seen in the elderly that affects the whole “organ” including cartilage, subchondral bone, synovium, and muscles. An increasing number of studies have suggested that the accumulation of senescent cells triggering by various stresses in the local joint contributes to the pathogenesis of age-related diseases including OA. In this review, we mainly focus on the role of the senescent skeletal cells (chondrocytes, osteoblasts, osteoclasts, osteocyte, and muscle cells) in initiating the development and progression of OA alone or through cross-talk with the macrophages/synovial cells. Accordingly, we summarize the current OA-targeted therapies based on the abovementioned theory, e.g., by eliminating senescent skeletal cells and/or inhibiting the senescence-associated secretory phenotype (SASP) that drives senescence. Furthermore, the existing animal models for the study of OA from the perspective of senescence are highlighted to fill the gap between basic research and clinical applications. Overall, in this review, we systematically assess the current understanding of cellular senescence in OA, which in turn might shed light on the stratified OA treatments.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21^−/−) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21^−/− and Ctsk-cre; Trim21^f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.