Identification of key genes underlying the effects of obesity on knee osteoarthritis
Knee osteoarthritis (OA) is a leading cause of disability worldwide, affecting over 300 million people—and obesity (BMI ≥30 kg/m²) doubles the risk of developing the disease. Yet exactly how excess weight triggers joint damage has remained unclear. A team of researchers from the Department of Rheumatology at the First Affiliated Hospital of Harbin Medical University in China set out to solve this puzzle by identifying the genes that link obesity and OA.
To find these genes, the team used a combination of powerful genetic tools. First, they turned to weighted gene co-expression network analysis (WGCNA), a method that groups genes into “modules” based on how often they’re active together—revealing which genes work as a team. They also compared gene activity between obese and non-obese OA patients to spot genes that change with weight.
The study used data from the Gene Expression Omnibus (GEO), a public repository of genetic research, specifically the GSE98460 dataset. This included 46 knee cartilage samples from 23 patients with end-stage OA (one sample from each knee’s medial and lateral tibial plateau, the areas most damaged in OA). After removing one outlier sample, the team focused on the 7,439 most variable genes (top 50%) to ensure reliable results.
To build a biologically realistic gene network, the team selected an optimal “soft-thresholding power” of 18—a value that ensures the network mimics how genes interact in real cells. This split the genes into 10 distinct modules. They then tested which modules were linked to BMI and found three (named light-green, salmon, and steel-blue) with a strong association (correlation >0.5, p <0.05). These three modules contained 458 genes—likely the ones connecting obesity and OA.
Next, the team analyzed what these 458 genes do. Using Gene Ontology (GO) analysis, they found the genes are involved in processes critical to OA: ossification (abnormal bone formation in cartilage), connective tissue development, reactive oxygen species (ROS) metabolism (cell damage from stress), and osteoblast differentiation (bone-forming cell growth). For example, too much ossification in cartilage (called endochondral ossification) can break down joints, while ROS damage the cartilage cells that keep joints healthy.
KEGG pathway analysis—another tool to map biological pathways—showed the genes are active in ribosome function (the cell’s protein-making factories), glutathione metabolism (an antioxidant pathway that fights ROS), and cell signaling (like MAPK and PI3K-Akt, which regulate cell growth and death). These pathways are all linked to how obesity stresses joints.
The team also compared gene activity between obese and non-obese OA patients. Using strict criteria (false discovery rate <0.05 and |logFC| ≥1—meaning genes were at least twice as active or inactive), they found 289 differentially expressed genes (DEGs): 146 more active in obese patients and 143 less active. These DEGs were linked to processes like immune cell migration (which drives joint inflammation) and apoptosis (cell death)—key drivers of OA progression.
To find the most critical genes, the team combined the 458 module genes and 289 DEGs into a protein-protein interaction (PPI) network using the STRING database (a tool that predicts how proteins interact). The network included 378 genes (nodes) and 895 interactions (edges). They then selected 30 “hub genes” (genes with >20 interactions, meaning they’re central to the network) and used the MCC algorithm (a way to rank gene importance) to narrow it down to 10 key genes.
These 10 genes—RPS5, RPL8, RPL17, RPL36, RPL18, RPL18A, RPL22L1, MRPL3, RPS19, and RPS9—all code for ribosomal proteins, the building blocks of the cell’s protein-making machinery. Ribosomes are underexplored in OA, but previous research suggests changes in ribosomal genes are a cell’s response to stress—like the extra pressure and inflammation from obesity. The team thinks these genes may drive endochondral ossification (abnormal bone growth) in cartilage, leading to OA.
While more experiments are needed to confirm these genes’ roles, the findings offer a new window into how obesity causes OA. The ribosomal genes the team identified could become targets for treatments that protect cartilage in obese patients—stopping OA before it starts.
This study was published in the Chinese Medical Journal in 2022 by Siming Dai, Juan Zhang, Xiaoying Zhu, Yuxuan Lin, Ying Cui, Zhiyi Zhang, and Zhiguo Lin.
doi.org/10.1097/CM9.0000000000001670
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