Source: Wiki Commons
While you all know me as a writer for Signals, I actually spend most of time working clinically. When wearing my health-care provider hat as a physician assistant in orthopaedics, I’m often asked about the use of stem cell therapy for the treatment of arthritis. Beyond the fact that stem cell therapy is not currently approved for arthritis treatment in Canada (with the exception of clinical research studies), I found that I didn’t really have much more information to offer patients. And I had questions of my own. So, I became inspired to learn more about the issue, and am now sharing this information with you!
What is the biological rationale for stem cells in treating arthritis?
Specifically, I’m referring to osteoarthritis (OA): degenerative (“wear and tear”) joint disease. Someone with OA can experience joint pain, stiffness and swelling, which can severely impact their daily activities and quality of life. Current treatments for OA include medications (anti-inflammatories), physiotherapy and injection therapies (corticosteroids, joint lubricants and platelet-rich plasma (PRP)). While these treatments can significantly improve symptoms and reduce inflammation, none can reverse OA. The closest thing to a “cure” is a total knee replacement (TKR), which has its own risks and limitations.
With the degenerative processes of OA resulting in the loss of cartilage (the softer substance that lines the joint), it would make sense for a treatment or cure to focus on rebuilding cartilage. Cartilage, comprised of collagen and other proteins, is integral to how mechanical forces are distributed through a joint. Chondrocytes, cells embedded within layers of cartilage, are responsible for its synthesis and maintenance. Their activity is influenced by mechanical and chemical stimuli, which regulate the constant balance of cartilage degradation and synthesis. With aging, we lose functional chondrocytes in the area of the joint that keeps the cartilage soft, and the balance tips towards degradation via aberrant activation of enzymes that break down collagen. This leads to increased stiffness of the cartilage, and its eventual calcification (bony transformation). This review is a great summary.
Chondrocytes are a terminally differentiated cell derived from mesenchymal stem cells (a.k.a. mesenchymal stromal cells or MSCs). After embryonic development, most MSCs become dormant, and produce new chondrocytes at a significantly slower rate (if at all). In theory, if active MSCs were introduced into a joint affected by OA, this could increase the number of healthy chondrocytes, thereby increasing cartilage production.
What is the clinical evidence for MSC-injection therapy in the treatment of OA?
A Stem Cell Research & Therapy article, published in early 2022, reviewed the published clinical trials for knee OA treatment with MSC injection, since its first use in 2008. The authors identified 23 Phase I/II trials – 13 randomized-control trials (RCTs) and 10 observational studies – whose goals were to demonstrate the safety and efficacy of MSC therapy. The studies varied in their source of MSCs (and associated preparation), dosage and injection regimen. The RCT control groups also differed, ranging from placebo or therapeutic injections to TKR. As you might imagine, it is difficult to extrapolate findings across such variation, particularly when the outcome measures themselves are variable! However, we can learn some general take-away points:
- Patients reported decreased pain, and improved range of motion and activity level, compared to baseline;
- Higher and/or repeated MSC injections resulted in improved pain and function at up to one-year follow-up (note: this is compared to saline or no injection);
- Patients reported increased benefit when MSCs were co-injected with hyaluronic acid (joint lubricant) or PRP, versus MSCs alone; and,
- Adverse events were minimal, and most often included transient joint pain and/or swelling.
In terms of joint regeneration and structure, there remains no evidence of cure. However, several studies reported that patients receiving the MSC therapy had less deterioration, improved cartilage quality (one and two), fewer areas of poor cartilage (based on MRI), or decreased pro-inflammatory markers in joint fluid (one and two), as compared to control groups or baseline. I’d like to highlight one study specifically – the only one to compare MSC injection to TKR. In this study, patients had OA in both knees, with similar symptoms, and were randomized to receive a TKR in one knee, and MSC injection into the other. Twenty-five of the 140 patients (18 per cent) ended up getting a subsequent TKR for the injected knee, an average of 10 years post-injection. Interestingly, many of these patients had more severe areas of OA at baseline. MSC therapy did not prevent needing a future TKR in all patients, but it was successful in delaying surgical intervention, with good interim symptom relief.
Why hasn’t this been approved in Canada?
While the above results certainly show that MSC injection therapy is on the right track as a potential treatment option for OA, they are far from sufficient for approval in Canada at this time. As indicated on the MyHealth Alberta patient information page, the research doesn’t demonstrate that MSCs can repair a joint already damaged by OA. The Ontario Institute for Regenerative Medicine doesn’t address MSCs and OA directly, but it does have a list of conditions that can be treated with stem cells and, sadly, OA is not one of them.
Aside from definitive evidence that MSCs work, there is a major practical limitation preventing their approval: no clear common standard for selection and preparation of MSCs is available. The International Society for Cell & Gene Therapy (formerly International Society for Cellular Therapy) has three criteria that must be met for a cell to be considered an MSC: 1) express certain cell surface markers; 2) be adherent to plastic; and 3) demonstrate in vitro differentiation into adipocyte, chondrocyte, and osteoblast lineages. However, there is no standard group of cell surface markers that can prospectively isolate an MSC population. Furthermore, there is no standard source from which to obtain MSCs: they can be derived from bone marrow, trabecular bone, adipose tissue (fat), synovial fluid, synovium, peripheral blood, or placenta. Each source requires the use of different markers and culture/isolations conditions, yielding cells with varying differentiation capacities. Before these clinical challenges can be addressed, we “simply” need to learn more about the pathophysiology of OA, and the mechanisms regulating MSCs.
Is there any indication as to the future of this therapy for use in Canada (or at all)?
Beyond participation in a clinical trial studying MSC therapy, there is no approved way to receive this treatment in Canada at this time. Any clinics offering stem cell therapy for OA (in and outside of Canada) are not supported by Health Canada, or any international regulatory bodies. Until the above questions are addressed, it will likely remain this way for some time.
Five years ago, there was a crack down by Health Canada on private clinics selling unapproved stem cell therapies to patients with OA. The therapies being marketed to patients as “stem cell” therapies (at a significant monetary cost), had never been tested either for safety or for efficacy, and were not proven MSC (or other stem cell) populations. Aspirations from a patient’s bone marrow or adipose tissue were simply spun in a centrifuge, which would isolate a substance that was theoretically “enriched” with stem cells, and was then injected into the patient’s joint. This is a bit of an approval loophole for cell-based therapies, as the cells injected underwent “minimal manipulation,” flying under Health Canada’s approval radar. However, there is no guarantee that the patients are getting what they paid for: a treatment that works or something that is safe. It remains a struggle to regulate these “stem cell” therapies, which unfortunately taints the work scientists are doing to move MSC treatment for OA forward.
Are there alternatives to stem cell therapy?
Researchers have several ideas for some non-cell-based therapies that work with the premise of MSCs. The first is to utilize growth factors that can bring a patient’s existing MSCs out of dormancy and push them to differentiate into chondrocytes. This is fairly limited from any clinical application as the molecular signalling pathways involved still need significant clarification. A second approach involves the use of MSC-secreted exosomes. Exosomes are essentially little packages filled with growth factors, enzymes and other proteins. MSCs release these into the extracellular matrix where they are able to interact with chondrocytes, and promote the constructive signalling pathways. Still under investigation in vitro, researchers hope that the use of MSC exosomes, rather than MSCs themselves, will be able to promote cartilage regeneration.
I wish that I could end this blog post with a more promising statement than “scientists are working on it!” But here we are. My personal opinion (as a non-expert in MSCs) is that the work around the combination therapies will come out on top someday. As we see in so many other conditions, combination therapy tends to do better than any therapy on its own. At the same time, OA might be something that can never be reversed, but only slowed. Hopefully having an impact on progression can reduce the need for surgery, and/or significantly improve the quality of life for those with OA.
Sara M. Nolte
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