Osteoarthritis (OA) is the most common joint disease, and good therapeutic results are often difficult to obtain due to its complex pathogenesis and diverse causative factors. After decades of research and exploration of OA, it has been progressively found that subchondral bone is essential for its pathogenesis, and pathological changes in subchondral bone can be observed even before cartilage lesions develop. Osteoclasts, the main cells regulating bone resorption, play a crucial role in the pathogenesis of subchondral bone. Subchondral osteoclasts regulate the homeostasis of subchondral bone through the secretion of degradative enzymes, immunomodulation, and cell signaling pathways. In OA, osteoclasts are overactivated by autophagy, ncRNAs, and Rankl/Rank/OPG signaling pathways. Excessive bone resorption disrupts the balance of bone remodeling, leading to increased subchondral bone loss, decreased bone mineral density and consequent structural damage to articular cartilage and joint pain. With increased understanding of bone biology and targeted therapies, researchers have found that the activity and function of subchondral osteoclasts are affected by multiple pathways. In this review, we summarize the roles and mechanisms of subchondral osteoclasts in OA, enumerate the latest advances in subchondral osteoclast-targeted therapy for OA, and look forward to the future trends of subchondral osteoclast-targeted therapies in clinical applications to fill the gaps in the current knowledge of OA treatment and to develop new therapeutic strategies.

Senile osteoporosis (SOP) is a systemic bone disease that is significantly associated with age and eventually leads to deteriorated bone strength and increased fracture risk. Urolithin A (Uro-A) is a gut microbiome-derived compound that is mainly produced from pomegranates and some nuts. Uro-A has attracted great attention in recent years in view of its protective effects on aging-related diseases, including muscle dysfunction, kidney disease and knee injury. However, its protective influence and possible mechanisms in senile osteoporosis remain unclear. Our study describes the beneficial effect of Uro-A on bone marrow macrophages (BMMs). The in vitro results demonstrated that Uro-A inhibited receptor activator for nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in BMMs in a concentration-dependent manner. Uro-A significantly reduced the expression of osteoclast-related genes and bone resorption. Mechanistically, we found that the autophagy ability of BMMs was significantly enhanced in the early stage of Uro-A treatment, accompanied by the activation of LC3 and Beclin 1. At the same time, this enhanced autophagy activity was maintained until the later stage after stimulation with RANKL. Furthermore, we found that the MARK signaling pathway was blocked by Uro-A treatment. In a mouse model of aging, Uro-A effectively inhibited bone loss in the proximal femur, spine and tibia of aging mice. These results indicated that Uro-A is a robust and effective treatment for preventing senile osteoporosis bone loss.

The ideal orthopedic implant coating is expected to both inhibit microbial infection and promote osseointegration. In this study, Zn ions were immobilized on a Ti substrate via a polydopamine (PDA) chemical surface modification to prepare Ti-PDA-Zn coatings. Scanning electron microscopy (SEM), atomic force microscopy (AFM), energy-dispersive X-ray spectroscope (EDS), X-ray photoelectron spectroscopy (XPS), contact analysis system, and inductively coupled plasma atomic emission spectrometry (ICP-AES) were used to analyze the morphology, composition, wettability, and zinc ions release of the coatings. The Ti-PDA-Zn coatings demonstrated excellent antibacterial activities in vitro against both Staphylococcus aureus and Escherichia coli. The coatings additionally displayed good biocompatibility, as confirmed by cytoskeletal observations and cell viability assays. Furthermore, the in vivo results confirmed the excellent antibacterial properties and improved osseointegration capability of the Ti-PDA-Zn coating in the presence of S. aureus. The present findings indicate that the Ti-PDA-Zn coatings prepared herein have potential application in orthopedic implantation.