Research News

A new study led by Suneel Apte, PhD, Department of Biomedical Engineering at Cleveland Clinic's Lerner Research Institute, along with Nicolas Piuzzi, MD, a physician-scientist and Program Director of Adult Joint Reconstructive Surgery Research, has identified significant mechanisms that lead to the progression of osteoarthritis. This first-of-its-kind study, which maps the breakdown of osteoarthritic cartilage and identifies a potential drug target to halt the progression of disease, was recently published in Osteoarthritis and Cartilage.

Osteoarthritis refers to the deterioration of joints, which begins with the gradual proteolytic (enzymatic) breakdown of protective cartilage at the end of bones. This novel study defined the landscape of osteoarthritic human knee cartilage using Terminal Amine Isotopic Labeling of Substrates (TAILS), a degradomics strategy that makes use of high-resolution mass spectrometry, as well as the precise role of the serine protease, HtrA1, in cartilage breakdown.

"We created a database of over 10,000 peptides, which are created during cartilage destruction by different proteases in osteoarthritis," says Sumit Bhutada, PhD, a postdoctoral fellow in Dr. Apte's lab. "After receiving cartilage samples, we prepared protein extracts for degradomics and then isolated the peptides that indicate cleavage sites. The Proteomics & Metabolomics Core took it from there."

Belinda Willard, PhD, Director of the Proteomics & Metabolomics Core, harnessed the expertise of the Core in designing experiments, processing samples and acquiring data on the mass spectrometer. The data generated provided the landscape of the proteins and peptides involved in the cartilage breakdown.

Translating Findings To Improve Patient Care

The team discovered nearly 11,000 cleavage sites in the osteoarthritis cartilage studied. Of these sites, 323 cleavages in 109 cartilage proteins were generated by the HtrA1 protease. Additionally, researchers found HtrA1 to be the most commonly detected and abundant protease in osteoarthritic cartilage. The identification of new osteoarthritis biomarkers and disease mechanisms, such as increased HtrA1, provides novel opportunities for managing this common disease.

As osteoarthritis progresses, symptoms may initially go unrecognized due to the slow rate of deterioration. Often, a formal diagnosis isn't made until the disease is advanced. By identifying biomarkers of cartilage breakdown, the team can sooner make a diagnosis, which they hope will slow down the progression of disease – lessening the likelihood of a joint replacement. Clinicians can potentially instead treat osteoarthritis with drugs like protease inhibitors that block the action of HtrA1. Targeting this protease is the next objective for Dr. Apte's team.

"It's all about having the right team – multidisciplinary teams of scientists and doctors working together with our patients' best interests kept front and center," says Dr. Nicolas Piuzzi. "That motivation, and support from a team, is key."

This research was made possible by funding from the Cleveland Clinic Musculoskeletal Research Center.