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The discovery of previously unknown cells could be the key to treating osteoarthritis (OA) in the 31 million Americans who suffer from the debilitating joint disease.
Researchers at Michigan Medicine identified cell types that emerge in joints after incidents of trauma and associated the cells with the degenerative disease process. The team published their research in Annals of the Rheumatic Diseases. The study examined the cellular and molecular changes that occur in joints during the onset of post-traumatic OA.
The researchers used cutting-edge single-cell RNA sequencing to discover cell types that emerge in the synovium after injury. “These cells are not found in healthy joints,” said Alex Knights, Ph.D., a senior postdoctoral researcher at Michigan Medicine who was involved in the research. “We must understand what causes the cells to appear and how they might cause OA.”
The researchers are also examining how the Wnt molecular signaling pathway is involved in the early activation of joint cells after injury.
Targeting a specific molecular signaling pathway is a selective approach to treating OA, according to head researcher Tristan Maerz, Ph.D., a biomedical engineer and Assistant Professor in the Department of Orthopaedic Surgery at Michigan Medicine.
It’s a process based on the important understanding that intact signaling is required for normal joint functioning. “We cannot shut down Wnt signaling in the joint,” Dr. Maerz said. “Therefore, we must find ways to target signaling mechanisms that cause it to be overactivated.”
SOX5 is among the transcription factors that might govern the emergence of pathologic fibroblasts in the synovium, according to Dr. Maerz. “We found that canonical Wnt signaling is overactivated in synovial fibroblasts,” he said. “The Wnt agonist R-spondin 2 is also highly expressed by a certain subset of fibroblasts.”
He said SOX5 and Wnt signaling might mitigate the overall disease process. “We are working with collaborators to develop treatments that target Wnt signaling and SOX5 in the joint,” he said. “The most important part of this work will be to establish dependencies and causality. Is Wnt signaling induction a consequence of the disease process, or a true driver of disease? Only if it is a driver of disease can it be a viable treatment target.”
The development of an intra-articular, slow-release drug treatment is another important aspect of the research. Dr. Maerz’s team is exploring the possible systemic administration of a drug targeting joint tissues. “This targeted approach would avoid the adverse effects of systemic treatment and reduce the burden of repeated joint injections,” Dr. Maerz said.
Dr. Maerz’s team received a $2.5 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to develop and test a biomaterial-based drug delivery system. The team will study the effects of the drug’s delivery kinetics, dosing and speed of release.
They hope to show that the treatment blocks Wnt signaling activation and mitigates overall disease severity. These findings would justify testing the drug in larger animal models and humans.
Joint injuries are occurring in increasingly younger individuals, according to Dr. Maerz. The onset of post-traumatic OA will continue, and the disease’s overall burden will increase dramatically over the coming decades. “Developing a treatment to block the disease process gives hope to OA patients,” Dr. Maerz said.
OA is often managed with physical therapy and pain medications but could progress to necessitate joint replacement surgery. “The disease is among the leading causes of disability worldwide. The population is aging, yet OA interventions are happening at increasingly younger ages,” Dr Maerz said. “Our work addresses one of the greatest and most urgent clinical needs.”
