Osteoarthritis, or OA, is one of the most common joint diseases worldwide, affecting millions of people, especially those over 65. It is a chronic condition that gradually damages joints, causing pain, stiffness, and reduced mobility. OA doesn’t just impact knees and hips—it can affect finger joints, thumbs, and even the spine. The symptoms are familiar: pain that worsens with movement, stiffness after sitting or resting, limited range of motion, and sometimes noticeable changes in the joints themselves. Unfortunately, OA is not just uncomfortable—it also carries a significant economic burden due to long-term treatment needs.
Traditionally, OA treatment has focused on managing symptoms, particularly pain. Anti-inflammatory medications, physical therapy, and lifestyle changes are standard approaches. While these strategies can improve quality of life, they do not address the root problem: the joint tissues themselves, including cartilage, ligaments, and menisci, cannot heal on their own. Once these tissues are damaged, OA progression continues, leading to further joint degeneration.
In this review, Harrell et al. evaluate current knowledge and future perspectives on the molecular and cellular mechanisms underlying the beneficial effects of MSCs in the treatment of OA.
The Role of Inflammation in Osteoarthritis
For many years, OA was thought to be simply a “wear-and-tear” disease. However, recent research has shown that inflammation plays a key role in the progression of OA. The early stages of OA involve the activation of the body’s immune system. Cells such as natural killer cells, macrophages, and mast cells respond to joint damage and produce molecules that can cause further tissue breakdown. Over time, the adaptive immune system becomes involved, with T cells and B cells contributing to chronic inflammation. These immune cells can produce autoantibodies, further harming cartilage and maintaining a cycle of inflammation.
This understanding of OA as an inflammatory disease has shifted the focus of treatment research. The goal is no longer just to relieve pain but also to reduce inflammation and encourage tissue regeneration.
Why Mesenchymal Stem Cells Are Promising
Mesenchymal stem cells, or MSCs, have emerged as one of the most promising tools in the fight against OA. These cells can be obtained from a variety of tissues, including bone marrow, fat, synovial tissue, and even muscles. MSCs have two key advantages that make them particularly useful in OA treatment. First, they can differentiate into chondrocytes—the cells that make cartilage—allowing them to potentially regenerate damaged joint tissue. Second, MSCs have immunomodulatory properties, meaning they can calm inflammation and reduce the immune system’s attack on joint tissues.
MSCs are relatively easy to obtain and grow in the lab. They can proliferate quickly, maintain their ability to differentiate even after multiple cell divisions, and are less likely to trigger immune rejection because they express low levels of certain immune molecules. These properties make MSCs a versatile and powerful option for treating OA.
How MSCs Help Repair Cartilage
For MSCs to be effective in repairing joints, they must turn into healthy cartilage cells. This process, called chondrogenic differentiation, is influenced by a variety of growth factors and environmental conditions. Proteins such as TGF-β, IGF-1, BMP-6, and others help MSCs develop into chondrocytes. Physical conditions also play a role: lower oxygen levels can encourage cartilage formation, and specialized scaffolds, gels, or hydrogels can provide structural support for growing tissue.
When MSCs successfully differentiate into chondrocytes, they produce important cartilage components like type II collagen and proteoglycans. Scientists are able to measure these markers in lab cultures to confirm that MSCs are developing into cartilage cells properly. Importantly, MSCs can do this without becoming hypertrophic, forming healthy cartilage rather than abnormal tissue.
MSCs and Inflammation Control
In addition to creating new cartilage, MSCs can help calm inflammation in OA joints. They interact with immune cells in two ways: directly through cell-to-cell contact and indirectly by releasing signaling molecules. MSCs can convert inflammatory macrophages into anti-inflammatory types, reduce the activity of natural killer cells, suppress autoreactive B cells, and promote regulatory T cells that help control immune responses.
MSCs release several molecules that contribute to this effect, including TSG-6, prostaglandin E2, and indoleamine 2,3-dioxygenase (IDO). These molecules reduce the production of inflammatory cytokines and encourage tissue repair.
MSC-Derived Exosomes and New Discoveries
Recent research has uncovered another exciting mechanism for MSC therapy: exosomes. These tiny vesicles, released by MSCs, carry proteins, microRNAs, and other molecules that influence surrounding cells. Exosomes from MSCs can promote chondrocyte growth, reduce apoptosis (cell death), and aid cartilage repair. Some studies have even identified specific microRNAs and long noncoding RNAs in exosomes that are especially effective in promoting cartilage regeneration.
In addition, MSCs can induce autophagy in damaged cartilage cells, a process that helps protect cells under stress. By enhancing autophagy, MSCs improve chondrocyte survival and support tissue repair, providing yet another therapeutic benefit.
Clinical Trials in Humans
Building on promising animal data, many clinical trials have explored MSC therapy in humans with OA. Bone marrow-derived MSCs (BM-MSCs) were among the first to be tested. In one early study, patients with knee OA received autologous BM-MSCs embedded in collagen gels. Over several weeks and months, the treated joints showed signs of cartilage repair and improved tissue quality compared to untreated controls. Patients reported reduced pain and improved function, and follow-up studies have shown that benefits can last for years.
Adipose-derived MSCs (AT-MSCs) have also been widely studied. These cells are easier to obtain in large quantities and have strong immunomodulatory effects. Clinical trials with AT-MSCs demonstrated improvements in pain, function, and cartilage health, even at relatively low doses. Some studies combined BM-MSCs and AT-MSCs to take advantage of both regenerative and immunosuppressive properties, demonstrating greater benefits for patients with moderate OA.
While most studies have focused on intra-articular injections directly into joints, percutaneous injections using the patient’s own growth factors have also shown promise. These methods rely on MSCs’ natural ability to home to damaged tissue, though controlling their migration remains a challenge. Using injectable carriers, such as hyaluronic acid, can improve MSC attachment and integration into damaged cartilage.
Allogeneic MSCs and Evolving Approaches to Cartilage Repair
Autologous MSCs are highly effective, but harvesting them can be invasive, and their regenerative capacity may be limited in patients with advanced OA. Allogeneic MSCs, derived from healthy donors, offer an “off-the-shelf” alternative. Early clinical trials using allogeneic MSCs have shown safety and some therapeutic effects, though immune responses can limit their long-term persistence. Strategies such as encapsulating MSCs in protective biomaterials may help prolong their survival and improve outcomes.
Researchers are also exploring ways to stimulate the body’s own MSCs to repair cartilage. Cell-free formulations such as BIOF2 can promote the expansion and differentiation of endogenous MSCs. Innovative surgical techniques, such as synovium brushing, are being tested to release MSCs from joint tissues, offering new avenues for cartilage regeneration without the need for cell transplantation.
The Future of Osteoarthritis Treatment
Osteoarthritis has long been a challenging condition with limited treatment options. Traditional therapies focus on managing symptoms but cannot repair damaged joints. Mesenchymal stem cells offer a promising new approach, capable of both regenerating cartilage and reducing inflammation. Research in animal models and human clinical trials has shown that MSCs can engraft in joints, promote tissue repair, modulate immune responses, and improve patient function.
Although challenges remain, including optimizing cell sources, doses, and delivery methods, the future of MSC therapy in OA looks bright. Ongoing studies are exploring ways to expand endogenous MSCs, improve allogeneic MSC survival, and harness MSC-derived exosomes for regenerative therapy. As our understanding of MSC biology grows, Harrell et al. believe these therapies may offer lasting relief and meaningful joint repair for millions of OA patients worldwide.
Source: Harrell, C. R., Simovic Markovic, B., Fellabaum, C., Arsenijevic, A., & Volarevic, V. (2019). Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomedicine & Pharmacotherapy, 109, 2318–2326. https://doi.org/10.1016/j.biopha.2018.11.099
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