Impact Stories

What led you to begin researching osteoarthritis?

I grew up and attended college and part of graduate school in China. On the first day of graduate school, my mentor introduced me to osteoarthritis (OA), a disease that has no available drugs for treatment. When he suggested I begin researching it, I said yes and I continued my graduate training in OA in the United States at Johns Hopkins University.

As I was about to complete my PhD, I came across review papers summarizing the progress in the field. It struck me that only ~10% of patients develop OA because of injury. Instead, the biggest risk factors for OA are aging and obesity, which are considered systemic risk factors, yet this area has been understudied. This drove me to postdoctoral training to study how aging, obesity and overall metabolism play a role in the progression of osteoarthritis.

What is the focus of your OA research?

When I first started working in the field, people thought that OA was just a cartilage issue — if you had a bad knee, it must be because the cartilage tissue is worn out. But the more I study OA, the more I find that cartilage is not the only tissue affected in the joint. For instance, the subcutaneous bone, a piece of bone underneath the cartilage, undergoes changes before you see any visible changes in cartilage. Obesity changes the loading impact on the subcutaneous bone and how it supports cartilage. Aging and obesity also cause inflammation in the synovial, the connective tissue in the joint, which impacts how the cartilage responds. In my lab, we are trying to better understand the role these tissues play in OA progression.

Another area of focus is on the metabolism of the cells inside the joint. Metabolic processes can be totally disrupted during the aging and obesity process. Our lab is working to determine if we can change the metabolic mechanisms and cure the disease.

Your lab was the first to observe SIRT5 decreases in cartilage during aging. What was your discovery?

SIRT5 is a protein that can control processes called protein post-translational modifications. That is when a protein inside a cell develops a tiny modification, which causes damage and decreases its enzymatic activity. SIRT5 is the joint’s defense system that can remove the modifications and restore the protein’s activity.

Our lab was the first to discover that SIRT5 decreases in cartilage during aging. Less SIRT5 leads to elevated levels of this modification, which we call lysine malonylation, or maK. We have also published findings that maK accumulates in the cells during aging and obesity. Using genetically modified mice and advanced imaging techniques, we discovered that if you delete the SIRT5 gene in the cartilage from mice, OA progression accelerates. It also accelerates in mice who are fed high-fat diets to induce obesity.

What are the potential implications of this discovery for patient care?

Most of us will develop OA in at least one joint as we age. Obesity is also a major risk factor in OA. If we can reactivate SIRT5 during the aging process, we may be able to correct metabolism and slow OA progression.

Secondly, while collaborating with a research group in Utah, we found a SIRT5 mutation in OA patients that causes decreased function of SIRT5. That means certain people are more vulnerable to OA. We foresee this discovery potentially providing one of the first genetic links between SIRT5 and OA disease in humans. This opens the door to developing screening tools to help identify high-risk patients, enabling earlier diagnosis and more personalized approaches to care.  

How has the Osteopathic Heritage Foundation’s funding investment furthered your research?

The Osteopathic Heritage Foundation’s funding has been transformative in my research and its potential to impact patient care. With this support, I have been able to establish a comprehensive research pipeline that integrates genetically engineered mouse models, state-of-the-art multiomics techniques and advanced imaging techniques to study how aging and obesity reprogram cartilage metabolism and drive OA.

Support from the Foundation also allowed us to discover SIRT5 and its role in cartilage metabolism. Building upon this work, the funding supported our work with collaborators in Utah, which led to the discovery of the SIRT5 mutation in human patients.

How has conducting research at a college of osteopathic medicine influenced your work?

Conducting research at the Heritage College deeply influenced how I think about OA. The focus of osteopathic medicine is on treating the whole person, recognizing that health and disease are influenced by interconnected systems rather than isolated organs and tissues. This philosophy parallels how we think in the OA field. We treat OA not simply as cartilage wear and tear, but as a systemic disease.

Where is your research leading next?

We are particularly excited about two promising avenues for translating our basic discoveries toward clinical relevance. The first is growth hormone. We studied all kinds of animals with various levels of growth hormone and concluded that, while excessive growth hormone can make you feel stronger, it contributes to joint disease, spine degeneration and tendon and tissue problems. This means that pegvisomant, an inhibitor for the growth hormone receptor, could potentially be repurposed for joint disease.

The second is a specific protein called acetyl-CoA carboxylase 1, or ACC1. It produces the precursors for the maK process, leading to the metabolic dysfunction of cells. We discovered that ACC1 gets upregulated during aging and obesity. If we can discover an inhibitor for ACC1, we can improve joint cell metabolism and protect against OA during aging and obesity.