Emerging metabolic pathways in osteoarthritis

 Osteoarthritis (OA) is one of the most prevalent conditions affecting tens of millions of U.S. adults, traditionally understood as a disease driven primarily by mechanical wear and tear. This perspective is being reshaped by emerging research that highlights the contribution of metabolic pathways to OA development and progression.

New research recently published in the journal Science, revealed compelling evidence of a gut-joint axis involving bile acid metabolism and glucagon-like peptide 1 (GLP-1) signaling in OA development. This study marks a significant advancement in understanding the metabolic underpinnings of OA and opens exciting new avenues for treatment along with potentially new possibilities for arthritis research at Yale.

Charles W. Ohse Professor of Orthopedics & Rehabilitation, Chuan-Ju Liu, Ph.D., serves as the vice chair of Research for the Department of Orthopedics & Rehabilitation and principal investigator at the Liu Lab for Translational Orthopedic Research.

His research efforts at Yale are centered on critical aspects of musculoskeletal health and disorders, particularly inflammation, age-related changes in joints and bones, and skeletal diseases. Of the many conditions he and his lab team prioritize, OA is paramount.

Liu, whose arthritis research is globally-recognized, was recently invited by the journal Science to write a Perspective article sharing his insights on this body of work.

Liu says, "The study by Yang et al shifts our understanding of osteoarthritis from a purely mechanical perspective to one that includes metabolic processes, potentially revolutionizing how we approach treatment."

The role of bile acid metabolism and GLP-1 signaling

According to Liu, the research by Yang and colleagues highlights the crucial role of bile acid metabolism, particularly glycoursodeoxycholic acid (GUDCA), in OA. Their preclinical studies showcased that reductions in GUDCA accelerated OA progression, while GUDCA supplementation mitigated these effects. This protective effect was primarily due to the inhibition of the intestinal farnesoid X receptor (FXR).

FXR, a key regulator of bile acid synthesis, lipid, and glucose metabolism, when inhibited, enhanced the proliferation of intestinal stem cells. This led to an increased number of enteroendocrine cells that secrete GLP-1, a hormone that enters the bloodstream and reaches the joints, thereby offering protection against OA by regulating cartilage-producing chondrocytes and other joint cells.

The influence of gut microbiome on osteoarthritis

The gut microbiome, particularly the bacterium Clostridium bolteae, plays an influential role in FXR signaling and GLP-1 modulation. Liu notes that Yang et al. demonstrated that C. bolteae disrupted bile acid balance, affected GLP-1 secretion, and altered OA progression. This intricate connection between the gut microbiome and joint health underscores the potential of targeting gut-derived pathways for OA treatment.

"The gut-joint axis is a relatively new concept but holds tremendous potential," Liu adds. "Understanding the role of the gut microbiome in osteoarthritis can lead to innovative therapeutic strategies."

Therapeutic potential of UDCA and GLP-1 receptor agonists

One of the most promising aspects of the findings, according to Liu, is the therapeutic potential of ursodeoxycholic acid (UDCA), a clinically approved drug for liver disorders. UDCA supplementation restored bile acid composition, increased GLP-1 levels, and subsequently reduced joint inflammation and cartilage degradation in preclinical trials.

Given that UDCA is already in clinical use, these findings offer a promising path for translation into OA treatment. Moreover, GLP-1 receptor agonists, such as semaglutide and liraglutide, widely used for diabetes and obesity, show potential in alleviating OA-related pain and could be explored further for their effects on cartilage integrity and joint structure.

Future directions and research opportunities

While UDCA has shown promise in mitigating OA progression in preclinical studies and observational human studies, further research is crucial to determine its long-term safety and efficacy in OA patients. Key questions remain, however, regarding the optimal dosing, duration of treatment, and the variability of responses among different patient subgroups based on their gut microbiome composition.

"Longitudinal clinical trials and advanced metabolomic profiling should be the focus of future research to refine patient selection criteria and optimize treatment protocols," says Liu.

"The concept of a gut-joint axis opens intriguing possibilities beyond osteoarthritis, potentially extending to other joint disorders such as rheumatoid arthritis and spondyloarthritis," he concludes. "The interplay between gut microbiota, bile acids, glucose homeostasis, and systemic immune responses is an emerging field that could uncover common therapeutic targets across multiple musculoskeletal diseases."

The evolving understanding of OA as more than a mechanical disorder, along with insights into the gut-joint axis, bile acid metabolism, and GLP-1 signaling, highlight a pivotal shift in the foundational understanding of the condition, which can be utilized to develop new, more effective therapeutic interventions that could significantly improve patient outcomes.

More information: Yuanheng Yang et al, Osteoarthritis treatment via the GLP-1–mediated gut-joint axis targets intestinal FXR signaling, Science (2025). DOI: 10.1126/science.adt0548

Chuan-ju Liu, Beyond wear and tear at the joint, Science (2025). DOI: 10.1126/science.adw4656

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