NSAIDs Reduce Therapeutic Efficacy of Mesenchymal Stromal Cell Therapy in a Rodent Model of Posttraumatic Osteoarthritis

Abstract

Background: Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis (PTOA). Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant. Hypothesis: NSAIDs will reduce the efficacy of hMSC therapy in treating a preclinical model of PTOA. Study Design: Controlled laboratory study. Methods: Lewis rats underwent medial meniscal transection (MMT) surgery to induce PTOA or a sham (sham group) surgery that did not progress to PTOA. Rats received naproxen solution orally daily before (Pre-NSAID group) or after (Post-NSAID group) hMSC treatment, throughout the course of the experiment (Full-NSAID group), or received hMSCs without NSAIDs (No NSAID). Cartilage morphology and composition were quantified using contrast-enhanced micro–computed tomography and histology. Pain (secondary allodynia) was measured using a von Frey filament. Results: Injection of hMSCs attenuated cartilage degeneration associated with MMT. hMSCs prevented proteoglycan loss, maintained smooth cartilage surfaces, reduced cartilage lesions, reduced mineralized osteophyte formation, and reduced pain by week 7. The Pre-NSAID group had decreased proteoglycan levels compared with the hMSC group, although there were no other significant differences. Thus, pretreatment with NSAIDs had minimal effects on the therapeutic benefits of hMSC injections. The Post-NSAID and Full-NSAID groups, however, exhibited significantly worse osteoarthritis than the hMSC-only group, with greater proteoglycan loss, surface roughness, osteophyte volume, and pain. Conclusion: Use of NSAIDs before hMSC injection minimally reduced the therapeutic benefits for PTOA, which included preservation of cartilage surface integrity as well as a reduction in osteophytes. Use of NSAIDs after injections, however, substantially reduced the therapeutic efficacy of cellular treatment. Clinical Relevance: Our data support the clinical recommendation of avoiding NSAID use after hMSC injection but suggest that using NSAIDs before treatment may not substantially diminish the therapeutic efficacy of cell treatment.

Safety assessment of equine allogeneic tenogenic primed mesenchymal stem cells in horses with naturally occurring tendon and ligament injuries

“…A single dose of NSAID was administered for animal welfare reasons, to avoid unnecessary pain and swelling due to the needle insertion all animals treated with intralesional injection (IVP and CP). The use of NSAIDs could potentially have a negative impact on the potency of MSCs ( 45 , 46 ), however It is unclear whether the concomitant use of NSAIDs interferes with the working mechanism of the tpMSCs. In the previously performed clinical field trial efficacy was demonstrated for tpMSC in naturally occurring tendon and ligament injuries, with statistically significant differences in all clinical and ultrasonographical parameters between the groups, as well as by significantly lower reinjury rate in tmMSCs treated horses in the long term ( 28 ).…”

Two Amnion-Derived Mesenchymal Stem-Cells Injections to Osteoarthritic Elbows in Dogs—Pilot Study

“…This means that the immunomodulatory effect of MSCs depends on the severity of tissue inflammation [ 137 , 138 , 139 , 140 , 141 ]. Another factor that can influence the study are NSAIDs, which were described as inhibitors of MSCs in vitro [ 142 ] and in vivo [ 143 ]. NSAIDs inhibit proliferation, differentiation, and migration of MSCs [ 144 , 145 ].…”

Revolutionizing orofacial pain management: the promising potential of stem cell therapy

“…A recent report indicates Proposed immune interactions of MSCs with host immune cells that lead to anti-inflammatory phenotype, the release of endogenous opioids, and pain relief. that the use of NSAIDs reduces the therapeutic efficacy of MSCs in a rodent OA model (136), suggesting a role of inflammatory response in MSC's beneficial effect. Thus, MSCs-produced pain relief is underlain by sophisticated reciprocal interactions between implanted cells and immune cells and the involvement of both pro-and anti-inflammatory mediators and their receptors.…”