Current understanding of osteoarthritis pathogenesis and relevant new approaches

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. In this review, we first focus on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, followed by a summary of several key mediators in OA-associated pain. We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain, such as CRISPR, scRNA sequencing, and lineage tracing. Next, we discuss the timely updates concerning cell death regulation in OA pathology, including pyroptosis, ferroptosis, and autophagy, as well as their individual roles in OA and potential molecular targets in treating OA. Finally, our review highlights new directions on the role of the synovial lymphatic system in OA. An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.

Osteoarthritis as an Umbrella Term for Different Subsets of Humans Undergoing Joint Degeneration: The Need to Address the Differences to Develop Effective Conservative Treatments and Prevention Strategies

“…This concept that OA is heterogeneous [ 14 , 15 ] and that sub-typing or phenotyping of OA is needed has also been raised by others [ 16 , 17 , 18 , 19 , 20 ] using a variety of criteria. Thus, some are related to metabolic phenotype [ 16 , 18 , 20 ], while others rely on patient characteristics at other levels [ 17 , 19 ].…”

Linear ubiquitination of LKB1 activates AMPK pathway to inhibit NLRP3 inflammasome response and reduce chondrocyte pyroptosis in osteoarthritis

“…The regulation of OA progression is also affected by pyroptosis [ 15 ]. Pyroptosis induces cell lysis, resulting in the massive release of pro-inflammatory factors and cellular contents.…”

“…Pyroptosis induces cell lysis, resulting in the massive release of pro-inflammatory factors and cellular contents. This promotes the development of many autoimmune and inflammatory diseases [ 15 ]. Pyroptosis was a programmed cell death signaling pathway required by Caspase-1 [ 16 , 17 ].…”

Pyroptosis in Periprosthetic Osteolysis

“…The inflammatory response around the joint prosthesis, especially the activation of macrophages, plays a key role in the occurrence and development of PPO [ 10 ]. Gasdermins family-mediated pyroptosis is a pro-inflammatory regulatory cell death mode that involves the caspase cascade and the activation and release of pro-inflammatory factors, such as IL1β/18 [ 11 , 12 ]. Nevertheless, the role of the pyroptosis in PPO still remains controversial.…”