Uncovering the Molecular Origins of Osteoarthritis

By Tiffany Parnell
Sunday, January 1, 2017

A causal relationship exists between senescent cells and osteoarthritis (OA) development, according to a recent study in The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. That finding confirms what researchers have long suspected.

The most common form of arthritis, OA affects about 31 million adults, according to the CDC. The disease causes significant pain and joint inflammation and is a leading cause of disability and healthcare expenditure in aging populations.

OA occurs when the articular cartilage that covers the bony surfaces within a joint begins to break down. The exact mechanisms responsible for OA development are unknown, but mechanical wear and tear and biological changes within the joint are both suspected of playing roles, according to Claudette Lajam, MD, orthopedic surgeon at NYU Langone Orthopedics. A review published in Best Practices & Research Clinical Rheumatology reports that age is the “single greatest risk factor for the development of OA.” Other risk factors include obesity, a history of joint injury and genetic predisposition.

The Cellular Senescence-OA Connection

With increasing age comes a greater accumulation of senescent cells. Those cells have undergone cell fate decision, no longer divide, are largely resistant to cell death, and produce a variety of inflammatory mediators that cause local inflammation and contribute to the deterioration of the extracellular matrix in cartilage and bone. Factors driving cellular senescence include potentially cancerous cell insults, such as DNA damage and the shortening of telomeres at the ends of chromosomes, as well as metabolic insults such as high blood glucose levels, says James Kirkland, MD, PhD, Director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic and senior author of the research study.

“These cells have been noted to accumulate around tissues in histological sections of joints from people who’ve had osteoarthritis and have a knee or hip replacement ...,” Dr. Kirkland says. “Whether they are a cause or an effect or an incidental finding with respect to osteoarthritis hasn’t been shown before. What we set out to do was show whether senescent cells in and of themselves could promote or cause the development of an osteoarthritis-like state. If so, that would argue that they contribute to the etiology and be one of the things that ties predisposition to osteoarthritis with chronological aging.”

Investigational Highlights

To explore the potential causal relationship between senescent cells and OA development, the research team injected 100,000 senescent or nonsenescent cells into and around the knee joints of mice, which rarely develop age-related OA. Cells used in the study were fibroblasts harvested from each animal’s ear cartilage. To induce cellular senescence, the cells were placed into culture and treated with either radiation or a chemotherapy drug. Seven mice received injections of senescent cells, and seven received injections of nonsenescent cells that were grown parallel in culture.

“There is a whole lot we don’t know about the development and progression of osteoarthritis. These studies ... that look at the causal factors will allow us to develop disease-modifying agents in the future [that] will be really life-altering for millions of people. There’s a lot of research to be done that could potentially have a great impact on the disease.”
— A. Holly Johnson, MD, Instructor in Orthopedic Surgery at Harvard Medical School, foot and ankle surgeon at Massachusetts General Hospital

Mice that received injections of senescent cells developed many of the hallmarks of OA, including pain in the knee joint and decreased joint functionality. Narrowing of the joint space, loss of bone near the knee joint and bony spurs were also observed on X-ray. The animals that received injections of nonsenescent cells exhibited no significant OA-related changes. In addition, pathologic changes associated with OA were observed in histological samples taken from mice that received the senescent cell injection.

A New Approach to OA?

The study’s results reveal that the accumulation of senescent cells in joints is indeed causal for OA, according to Dr. Kirkland. Based on these results, treating OA with drugs that target senescent cells may help slow progression of the disease, a condition for which there are no approved disease-modifying drugs.

Senolytic drugs — a new class of pharmaceutical agents that were developed in 2015 and help destroy and remove senescent cells — may hold the key to treating age-related OA. Moving forward, research that tests whether or not senolytic drugs help prevent, delay or treat OA in animal models is necessary. If animal trials are positive, clinical trials in humans will likely follow, according to Dr. Kirkland.

Current OA treatment strategies are not curative. They include weight loss, physical therapy, and the use of nonsteroidal anti-inflammatory medications, corticosteroid injections, braces and/or assistive devices. In cases of end-stage, or bone-on-bone, OA, joint replacement surgery may be recommended.

Due to advances in surgical technique and implant technology, joint replacement is a safe and long-lasting solution for hip and knee OA. However, joint replacement surgery is often used more discriminately and may not be as effective in treating OA in other joints, such as the ankle. Ankle implants, for example, usually last only 10 years in ideal scenarios. Disease-modifying, senolytic agents may be an important complement for OA treatment, especially in joints that may not respond as well to surgery.

“We have excellent surgical treatment strategies that are very successful and relieve pain, improve function, and get people back to work and back to their lives ...,” Dr. Lajam says. “However, there’s always room for improvement, and we’re continuing as orthopedic surgeons to look for those. ... We hope in the future that we will have some even better solutions.”