Pathogenesis of Osteoarthritis

Current Models for Development of Disease-Modifying Osteoarthritis Drugs

Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Notably, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine.

Role of mitochondria in mediating chondrocyte response to mechanical stimuli

Given that diarthrodial joints primarily display the weight-bearing and movement-supporting function, it is not surprising that mechanical stress represents one of the major risk factors for osteoarthritis (OA). However, the inner connection between mechanical stress and OA onset/progression has yet to be explored. Mitochondrion, a widespread organelle involved in complex biological regulation processes such as adenosine triphosphate (ATP) synthesis and cellular metabolism, is believed to have a controlling role in the survival and function implement of chondrocytes, the singular cell type within cartilage. Mitochondrial dysfunction has also been observed in osteoarthritic chondrocytes. We systemically summarize mitochondrial alterations in chondrocytes during OA progression and discuss our recent progress in understanding the potential role of mitochondria in mediating mechanical stress-associated osteoarthritic alterations of chondrocytes. We also propose the potential signaling pathways that may regulate this process, which provide new views and therapeutic targets for the prevention and treatment of mechanical stress-associated OA.

Novel role of estrogen receptor-α on OA pathogenesis

Currently, there are no therapies that can halt or reverse the progression of osteoarthritis (OA).  In this study, we found level of estrogen receptor α (ERα) was significantly reduced in severely damaged cartilage of osteoarthritic knees when compared to the relatively preserved cartilage from the same knee. Knockdown of ESR1, the gene encoding ERα, resulted in an upregulation of senescence- and OA-relevant markers in chondrocytes. Conversely, knockin of ESR1 partially reversed the osteoarthritic and senescent phenotype of OA chondrocytes. Using a three-dimensional (3D) culture model, we demonstrated that mechanical overload significantly suppressed ERα level in chondrocytes with concomitant upregulation of osteoarthritic phenotype. When ESR1 expression was suppressed via siRNA, mechanical loading enhanced hypertrophic and osteogenic transition. Taken together, our study demonstrates a new estrogen-independent role of ERα in mediating chondrocyte phenotype and response to mechanical loading, and suggests that enhancing ERα level may represent a new method to treat osteoarthritis.​