Cite as: Buchheit T, Eshraghi Y. Regenerative therapies for arthritis: mechanisms of analgesia. ASRA News 2021;46. https://doi.org/10.52211/asra080121.051. 

Osteoarthritis is the most significant cause of disability and economic burden in older adults¹; as patients search for effective nonsurgical remedies, intra-articular regenerative therapies are an increasingly common option. These biologically based treatments include cellular products derived from bone marrow, lipid, and other tissues, and blood-derived products such as platelet-rich plasma (PRP) and autologous conditioned serum (ACS).

Inflammation serves as a driver of osteoarthritic pain and is a frequent target for research and therapy; ^2,3 catabolic cytokines such as TNF, IL-1 and enzymes such as matrix metalloproteinases are associated with pain and joint degeneration; ^4,5 conversely, anabolic cytokines such as IL1-Ra (an inhibitor of IL-1), TGF-ß, IL-10, and others are protective for joint tissue.^6,7 It is the proper balance of these factors that is the goal of regenerative medicine.

PRP and Growth Factors

Platelets contain over 300 growth factors such as transforming growth factor-ß (TGF-ß), platelet-derived growth factor, fibroblastic growth factor, hepatocyte growth factor, epidermal growth factor, and others.^8-10 In most PRP preparations, white blood cells (WBCs) such as neutrophils and monocytes are also present in varying concentrations. WBCs may provide a pro-inflammatory stimulus,¹¹ but also play a role in repair mechanisms after injection. In particular, monocytes and macrophages may function as inflammatory cells or inflammation-resolving cells and are capable of activating a therapeutic response through growth factor expression and recruitment of endogenous hematopoetic stem cells to the site of delivery. ^12–14 The evidence supporting PRP’s therapeutic benefit in arthritis pain is increasingly established but variable depending on the specific indication. ^15,16

ACS, Anti-Inflammatory Cytokines, and Growth Factors

In the 1990s, investigators found that incubated whole blood was a significant source of anabolic cytokines such as IL1-Ra, IL-4, IL-10, and TGF-β. ^7,17 More recent research findings show that the incubation process as well as cell culturing may induce the production of exosome-containing micro-RNA that drives beneficial epigenetic changes in the target tissue.^{18, 19}  ACS has demonstrated longer-term benefit in knee^7,20,21 as well as hip arthritis.²²

Mesenchymal (Stem) Cell Therapies and Immune Modulation

Mesenchymal cells may be derived from multiple sources, including bone marrow, adipose, and umbilical cord, and are often described as MSCs, a broad acronym that signifies either mesenchymal stem cells, mesenchymal stromal cells, or medicinal signaling cells. ^23,24 The cell lines may differentiate to cartilage, muscle, and bone, given appropriate cell culture media,^24,25 although in clinical use, MSCs often are injected immediately after harvest (non-cultured cells). Meta-analyses support a positive analgesic response for the treatment of knee OA,^26-27 and observational data suggest improvements in cartilage health following treatment with culture-expanded MSCs;^28,29 however, it does not appear that tissue engraftment occurs, particularly with non-cultured cells.

Recent study findings increasingly support the importance of cytokine and immune activity in the therapeutic response following MSC treatment to an arthritic joint.^30-33 These immune mechanisms of action have been further clarified with the experimental use of infused MSCs that induce a phenotypic change in circulating macrophages, subsequently upregulating anabolic and anti-inflammatory cytokines such as IL10 and TGF-b.³⁴ Furthermore, it is possible to reverse the analgesia of cultured laboratory MSCs with the use of an antibody to TGF-b.³⁵ Clinically, this immune-driven analgesic mechanism is supported by a study demonstrating that the majority of patients who experienced positive clinical outcomes after MSC injection had no improvement in cartilage abnormality.³⁶

Conclusion

Despite the diversity of methods and applications used in regenerative pain medicine, common analgesic processes—including growth factor augmentation, immune modulation, and epigenetic target-cell changes—likely play a critical part in outcomes following the application MSCs, PRP, and ACS as well as other biologically based treatments. Regenerative medicine holds great promise in the treatment of degenerative musculoskeletal conditions, but more work is needed to clarify the fundamental mechanisms common to these evolving arthritis treatments. 

Thomas Buchheit, MD, is the director of Regenerative Pain Therapies at the Center for Translational Pain Medicine in the department of Anesthesiology at Duke University and Durham Veterans Affairs Health Care System in Durham, NC.

Yashar Eshraghi, MD is the medical director of Pain Research, assistant program director of the Pain Medicine Fellowship Training Program, and assistant professor in the department of Anesthesiology and Critical Care Medicine at Ochsner Health System at the University of Queensland Ochsner Medical School. He is also a clinical assistant professor at Louisiana State University School of Medicine in New Orleans.

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