Researchers have identified 13 genes that may play key roles in osteoarthritis risk and progression, including 6 previously unknown genetic targets, according to a new study.
In the study, published in Cell Genomics, the research team, led by investigators at the University of North Carolina, analyzed gene expression, chromatin accessibility, and three-dimensional chromatin structure in human chondrocytes (cartilage cells) under both normal and osteoarthritis (OA)-like conditions. Their findings provided new insights into how genetic variations influence OA development and potential therapeutic approaches.
"This study represents a major breakthrough for OA research by providing potential explanations for 13 OA [genome-wide association study] risk loci," the study authors wrote. "The next critical steps are to functionally characterize the roles that these genes play in the OA phenotype and determine if modulating their expression or activity can alleviate or even reverse OA-related symptoms," they added.
The study examined chondrocytes from 101 human donors, treating the cells with either a control solution or fibronectin fragments that simulate OA conditions. Using advanced genomic techniques, the researchers identified thousands of genes that showed altered expression patterns based on age, sex, and disease state.
One particularly promising discovery centers on the gene PAPPA, which showed increased expression in both OA tissue and older donors. The researchers found that PAPPA was connected to its genetic regulatory regions through a complex three-dimensional chromatin structure spanning over 400,000 DNA base pairs.
The study revealed that many genetic variants associated with OA risk affected gene expression differently under normal vs disease-like conditions. This finding suggested that the timing of therapeutic interventions may be crucial for treatment success.
"While it is reasonable that some genes may influence OA risk by the role they play in response to cartilage matrix damage, it is also plausible that years of aberrant gene expression could predispose a [patient] to OA," the study authors noted. "For example, a lifetime of heightened expression of a proinflammatory gene could lower the barrier to cartilage degradation," they continued.
The research may have immediate implications for drug development, as it identified specific molecular pathways that could be targeted for OA treatment. Among the novel genes identified, several were found to be involved in processes known to influence joint health, including inflammation control and cartilage maintenance.
The study also provided evidence that genetic risk factors for OA may operate through multiple distinct biological processes rather than a single pathway, suggesting that successful treatment strategies may need to be personalized based on individual genetic profiles.
This study was among the largest analyses in OA research and identified genetic targets that could inform drug development efforts. Tissue samples were provided by the Gift of Hope Organ and Tissue Donor Network, and the research was supported by NIH grants and the National Center for Advancing Translational Sciences.
According to the researchers, additional studies are required to translate these findings into effective treatments. They highlighted the need for functional characterization of the identified genes and evaluation of their therapeutic potential.
The authors declared no competing interests.