A Novel Microvesicle-Based Therapeutic Strategy of Osteoarthritis
Abstract
This proposal has two immediate goals regarding the potential therapeutic utility of microvesicles (MV) on OA. MV is formed by budding directly from plasma membrane of living cells and is a major form of the released extracellular vesicles (EV), which are nanosized, plasma membrane-bound vesicles released by cells that transport DNA, RNA, or protein biological cargoes between distant cells as a form of intercellular communication. Our first goal is to establish that MV released by bone destruction cells (osteoclasts) can act on chondrocytes to promote the repair of the damaged articular cartilage and on cells of synovium to suppress the acute and chronic inflammation in response to osteoarthritis (OA). It also acts on bone cells to rebuild the degenerated bone structures underneath the articular cartilage (subchondral bone). We believe that these skeletal activities would allow the MV to simultaneously address three important but distinct etiologies of OA, rendering it an excellent candidate for a comprehensive therapy for OA. Thus, our second goal is to evaluate the feasibility of the MV-based therapy for OA. Accordingly, this proposal is related to the Fiscal Year 2022 Peer Reviewed Medical Research Program Portfolio of Orthopaedic Medicine, Topic Areas of Arthritis and Musculoskeletal Disorders, and Strategic Goal of development and testing of novel and improved intraarticular treatments for joint injuries. Articular cartilage is a white, dense, specialized connective tissue covering the bony articulating ends inside the joint, and its primary function of articular cartilage is to provide cushion and lubrication to facilitate natural joint motion. Injuries to the joints, chronic or increased joint loading, or genetic predisposition can lead to lesions of the articular cartilage, which often causes acute and chronic synovial inflammation and OA. OA is the most common degenerative joint disease and afflicts ~50 million people annually in the United States alone. An estimated 12% (or ~6 million) of all OA are resulted from an acute trauma event to the joint and are referred to as PTOA. The estimated aggregate financial burden specifically of OA/PTOA (in 2011) is >3.06 billion dollars annually. While primary OA affects mostly people older than 60 years, PTOA can afflict younger and more physically active population. Due to the high physical demands of military-related training and activities or to combat-related traumatic injuries to the joints, the military population has a much greater incidence of PTOA than the general population. There is no cure for OA/PTOA. Current therapies are limited to pain management and inflammation reduction. The highly invasive surgical alternatives are unable to restore a normal cartilaginous surface and suffer from poor integration with the surrounding host bony tissues. The frequent eventual endpoint is joint replacement with a prosthetic device or even amputation, which are not viable options for young or middle-aged patients. It is speculated that a major reason for the lack of a highly effective therapy for OA is because OA is a multifaceted disorder, involving many complicated etiologies. Thus, a comprehensive therapy for OA is one that can simultaneously address most major etiologies of the diseases, e.g., (1) persistent erosion of articular cartilage due to acute and chronic inflammation of the injured/damaged synovium; (2) inability of the damaged articular cartilage to repair itself; and (3) dysfunctional remodeling of subchondral bone structure. Unfortunately, no current approved therapy can address more than one etiology. As a result, the benefit of the current therapies is often transient, marginal, and unsatisfactory. This proposal has advanced two novel concepts: The first concept is that osteoclastic MV has potential pro-chondrogenic, anti-inflammatory, and osteogenic activities in relevant cells within the injured joint. This concept was based on the recent preliminary f
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310061
Entities
People
- Kin-Hing Lau
Organizations
- Jerry L. Pettis Memorial VA Medical Center
- United States Army