A novel small molecule screening assay using normal human chondrocytes toward osteoarthritis drug discovery.

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability in adults. A central feature is progressive cartilage degradation and matrix fragment formation driven by the excessive production of matrix metalloproteinases (MMPs), such as MMP-13, by articular chondrocytes. Inflammatory factors, including interleukin 6 (IL-6), are secreted into the joint by synovial fibroblasts, and can contribute to pain and inflammation.

3D chromatin structure in chondrocytes identifies putative osteoarthritis risk genes.

Genome-wide association studies have identified over 100 loci associated with osteoarthritis risk, but the majority of osteoarthritis risk variants are noncoding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multiomic approach and genome editing to identify and functionally characterize potential osteoarthritis risk genes. Computational analysis of genome-wide association studies and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for osteoarthritis risk variants.

Overexpression of Peroxiredoxin 3 in Cartilage Reduces the Severity of Age-Related Osteoarthritis But Not Surgically Induced Osteoarthritis in Mice.

Objective: The study objective was to determine whether overexpression of the mitochondrial antioxidant peroxidase, peroxiredoxin 3 (Prx3), reduces the severity of osteoarthritis (OA) in mice.

Methods: Age-related OA (age 18 and 24 months) and OA induced by destabilization of the medial meniscus (DMM at age 6 months) were assessed in male mice that overexpress a human Prdx3 transgene encoding the Prx3 protein. Lox-stop-lox-Prdx3 (iPrdx3) mice were crossed with aggrecan-Cre mice to produce iPrdx3AgCre or with Col2Cre to produce iPrdx3Col2Cre mice.

Mechanisms and therapeutic implications of cellular senescence in osteoarthritis.

The development of osteoarthritis (OA) correlates with a rise in the number of senescent cells in joint tissues, and the senescence-associated secretory phenotype (SASP) has been implicated in cartilage degradation and OA. Age-related mitochondrial dysfunction and associated oxidative stress might induce senescence in joint tissue cells. However, senescence is not the only driver of OA, and the mechanisms by which senescent cells contribute to disease progression are not fully understood.

Autophagy regulates the localization and degradation of p16.

The tumor suppressor protein p16 (p16) is a well-established hallmark of aging that induces cellular senescence in response to stress. Previous studies have focused primarily on p16 regulation at the transcriptional level; comparatively little is known about the protein's intracellular localization and degradation. The autophagy-lysosomal pathway has been implicated in the subcellular trafficking and turnover of various stress-response proteins and has also been shown to attenuate age-related pathologies, but it is unclear whether p16 is involved in this pathway.