A new study published in Nature Biomedical Engineering, by researchers at Hospital for Special Surgery (HSS) and others has identified a gene pathway involved in the formation of fibrous scar tissue that represents a major cause of failed joint replacements. Findings demonstrated this fibrosis can be prevented and even reversed by blocking the pathway, potentially opening the door to improved surgical outcomes in these patients.

Loosening of joint implants, such as hips and knees, without infection or trauma is responsible for as many as 40 percent of failed joint replacements. In these cases, called aseptic loosening, scar tissue accumulates around the implant instead of the bone, preventing the new joint from regaining stability. Revision surgery to remove the original implant, clear the fibrosis and place a new prosthesis can correct the problem. However, avoiding a second operation, and the strain of additional recovery, would be a preferred option.

“Revision surgery is akin to pressing a ‘reset button’ on the cells in the patient’s body, in the hopes that this time the cells will correctly form bone around the implant rather than fibrous tissue,” said Vincentius (Jeremy) Suhardi, MD, PhD, an orthopedic surgical resident at HSS, and first author of the study.

 Using a preclinical model to simulate joint replacement surgeries in people, Suhardi and the team of investigators discovered that a group of cells involved in the production of new bone are also responsible for forming scar tissue around joint implants.

“We found that local bone progenitor cells, specifically leptin receptor-expressing cells, are necessary and sufficient for scar tissue formation around the implant that leads to aseptic loosening,” Dr. Suhardi said.

The researchers showed that the leptin receptor-expressing cells activate a gene/protein pathway called Adhesion G Protein-Coupled Receptor F5 (ADGRF5). They also found that blocking the ADGRF5 pathway with daily intra-articular injections of an antibody that inhibits the gene can both prevent fibrous tissue from forming and shrink existing fibrosis in the area of a joint implant. Blocking ADGRF5 in preclinical models also increased the formation of peri-implant bone.

“This finding for the first time opens up the possibility of treating aseptic loosening with a drug that inhibits ADGRF5,” Dr. Suhardi said. We are planning to collaborate with strategic partner to further develop this therapy and to test its efficacy not just in aseptic loosening but also in other orthopedic-related fibrotic pathologies.