Uncovering the Role of Fat in Knee Pain: HIVE Researcher Takes a Whole-Body, Bioengineering Approach

One in four Americans over age 50 experiences frequent knee pain that limits mobility and reduces their quality of life. Yet most patients must tough it out until their pain is debilitating enough to justify knee replacement surgery, an invasive solution with drawbacks of its own. UCSF researcher Kelsey Collins, PhD, aims to change that. She’s pioneering research that explores how the body creates and manages knee pain, and exploring engineering-based solutions to reduce pain.

"There’s a big gap in our understanding of musculoskeletal conditions like osteoarthritis, which is the leading diagnosis for knee pain. We do know that knee pain cannot always be ‘fixed,’ even surgically. Given how common this pain is, it’s also a significant driver of the opioid epidemic,” says Collins, assistant professor and director of the laboratory for musculoskeletal crosstalk in the UCSF Department of Orthopaedic Surgery. 

A holistic look at pain

"We’re looking at osteoarthritis as a model to understand chronic pain,” she says. Because obesity is a frequent comorbidity to osteoarthritis, Collins and her group have uncovered a role for factors secreted by fat fat in knee pain. Osteoarthritis (OA) has been believed to be a problem of a single tissue, like cartilage, or a single joint, like the knee. It is not usual to study blood or tissues outside the knee joint, like fat.
 

"We first started looking at the role of fat in osteoarthritis when it became clear that many patients have co-morbid conditions with osteoarthritis like obesity, metabolic syndrome, diabetes, and cardiovascular disease. For a long time, fat was thought of as just this extra inert tissue that wasn’t needed. Now we know that fat plays several critical roles in our bodies and signals other functions relevant to how pain and OA develops and persists,” says Collins. “We want to learn how to modify fat tissue to reduce knee pain. The most exciting part about this approach is that the signals from fat we are measuring are involved in many diseases, including aging, cancer, cardiovascular disease, and diabetes — so solutions that involve re-wiring fat have broad applications to chronic diseases.”

Collins’ recent research, published in Science Advances, manipulated mice by giving them knee injuries and controlling the amount and type of fat in their body. The study built on existing findings about the role of leptin, a hormone produced by fat cells that helps regulate appetite but also promotes inflammation, in osteoarthritis. She found that leptin alone doesn’t tell the full story. Her team identified another fat-secreted factor — complement factor d — that uniquely increases pain in response to knee injury.

"Our results are a key step in understanding what causes knee inflammation and pain, so we can create therapies that rewire fat to behave better and reduce pain,” Collins says. “The potential impact is broader than osteoarthritis and knee pain, which is why it’s important that this work is published in a general scientific journal like Science Advances. This work highlights that osteoarthritis can be used as a model to study complex and interconnected biology that is the result of signals from fat tissue.”

Bioengineering new solutions

Teaching tissues to behave in different and better ways will require an engineering strategy, says Collins, which is why her partnership with UCSF’s Health Innovation Via Engineering (HIVE) center is so important to her research. She used several new technologies that are engineering-based, including leveraging a sequencing technique called spatial transcriptomics — this paper is among the first published examples of using that approach to look at which tissues are changing in a high resolution manner. Her team also used osmotic pumps in mice that lack fat, and created new pain measurement processes for this study.

"The best part about being a bioengineer is that we’re not afraid to develop and adapt tools to answer tough questions,” says Collins. “HIVE creates an environment where people can work together to think about complicated problems, develop new tools, and share techniques and protocols to execute studies like this.”