Stem Cell Therapies for Replacing Cartilage in Arthritis

Stem cells have been found to target inflammation in osteoarthritis or rheumatoid arthritis.

Stem cells have been found to target inflammation in osteoarthritis or rheumatoid arthritis.

According to the CDC, osteoarthritis (OA) affects more than 13% of adults over the age of 24 years, and more than one-third of adults over the age of 65 years. As the population ages, the burden of OA is expected to increase. OA is not simply a condition that affects quality of life. It is also associated with higher mortality, including increased all-cause mortality, increased cardiovascular mortality, and a greater risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastropathy.

Unfortunately, at present, few targeted therapeutic options are available for relieving the pain associated with OA. However, scientists are working on targeted treatments to help reverse the cartilage degeneration in patients with this common, debilitating condition.

To date, stem cell therapies for treatment of OA has been limited to use in dogs, and in other animals such as competitive racehorses. Questions remain about the safety of these therapies. In fact, in 2012, the FDA released an advisory regarding unapproved stem cell therapies due to concerns about safety and uncertainty about the efficacy of different types and lines of stem cells in inducing cartilage repair in OA.

Multipotent mesenchymal stem cells, or MSCs, have been studied as promising candidates for treatment of OA, and other forms of arthritis in humans. These cells have been shown to target areas of tissue damage and inflammation, such as inflamed joints in OA or rheumatoid arthritis. Important questions remain about effects on other tissues, however. In addition, the mechanism of MSCs targeting articular cartilage remains unknown.

In early trials, MSCs have been administered directly into damaged joints, and have also been administered systemically. With systemic administration, certain ligand and growth receptors on the surface of MSCs may have a role in targeting damaged tissues. Particularly important in these homing processes are the chemokine receptors 1 and 2, as well as endothelial growth factor receptor 1, and the platelet-derived growth factors A and B, among others.

Current theories of MSC homing suggest that release of these factors from inflamed portions of the joint space help set up a chemotactic gradient that leads stem cells to preferentially diffuse into inflamed synovial joints. With a greater understanding of these growth factors in MSC homing, scientists could amplify the homing effects of MSCs using genetic engineering techniques. In addition, artificial gradients could be set up by injecting analogs of such homing factors into inflamed joints.

These targeting mechanisms could find applications in other disease states, and in delivery of targeted biological agents and drugs to specific sites, such as the pancreas in type 1 diabetes, for instance.

In addition, if current treatments such as tumor necrosis factor (TNF) inhibitors, commonly used in RA interrupt MSC homing, understanding the mechanism of homing is important in determining how to use MSC therapies. For instance, a TNF inhibitor might be discontinued before attempting targeted therapies with MSCs.

According to a search of ClinicalTrials.gov on July 9, 2015, a total of 2 phase 3 trials (NCT01626677, NCT01873625) investigating the effects of MSCs in osteoarthritis are either in progress, or have been completed. Primary results of the CARTISTEM trial were expected in May 2015, but reporting has been delayed by data collection procedures. Final results of an Iranian trial with MSCs for repair of OA were complete in 2011, but have not been reported in mainstream medical literature. Considering that these treatments are already in veterinary use, however, it is likely that the treatments will also be effective in humans.

References

  • CDC. Arthritis. http://www.cdc.gov/arthritis/basics/osteoarthritis.htm. Accessed July 2015.
  • de Bakker E, Van Ryssen B, De Schauwer C, Meyer E. Canine mesenchymal stem cells: state of the art, perspectives as therapy for dogs and as a model for man. Vet Q. 2013;33(4):225-233.
  • FDA. FDA Warns About Stem Cell Claims. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm286155.htm. Accessed July 2015.
  • Eseonu OI, De Bari C. Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis. Rheumatology (Oxford). 2015;54(2):210-218.
  • ClinicalTrials.gov. Records NCT01626677 and NCT01873625. Accessed July 2015.