Mesenchymal Stem Cells: Vanquisher Or Accomplice Of Osteoarthritis?

Minji Ai discusses osteoarthritis, mesenchymal stem cells, and and how our mechanistic understanding of them both is bringing us closer to a therapy currently just out of reach

Osteoarthritis | Is there an old lady living next door to you who complains about joint pain every winter as the temperature drops? If so, she may have arthritis. Osteoarthritis is the most common form of arthritis affecting over 250 million people worldwide, particularly the elderly. In the UK, one in three adults aged 45 and over have reported osteoarthritis symptoms, 60% of which are in the knee joint. Primary osteoarthritis symptoms include chronic pain and stiffness in joints, which hugely impair one’s mobility and quality of life.

How does osteoarthritis become established in joints? To answer this, we need to first understand how a healthy joint functions. A joint is a connective structure where two bones meet. A typical moving joint, such as the knee joint, consists of bones, articular cartilage covering bone ends, a synovial capsule forming the joint cavity, and connective tissue linking the two bone ends.

Similar to the renewal of our red blood cells, joint tissues also renew, albeit at a much slower pace. It takes nearly 25 years for proteoglycan, a main component of cartilage, and 10 years for bone to renew in adults. Underlying this slow self-renewal process is the constant breaking down and regrowth of tissue components, termed as turnover, which is regulated by tightly controlled biological mechanisms.

This renewal process can be easily disrupted, leading to diseases such as osteoarthritis. Osteoarthritis arises from abnormal joint tissue turnover, which can be triggered by various factors such as ageing, obesity, joint injury, or overuse of joints. These skew the renewal balance in cartilage and bone, leading to typical osteoarthritis-like features such as cartilage loss and abnormal bone growing in the joints. Such features progress slowly over time as highly differentiated cartilage and bone cells have a limited capacity to stop or reverse this skewed turnover.

Treatments For Osteoarthritis | Sadly, there is currently no cure for osteoarthritis. There are treatments available for symptom relief and joint function improval. Physical therapy and pain relief medication are usually prescribed to patients with moderate osteoarthritis. Invasive surgical methods such as joint replacement surgery are recommended to patients with advanced osteoarthritis. However, these treatments

have limitations. Long-term use of pain relief medication comes with the risk of addiction or cardiovascular disease development, while surgeries may come with complications. Recently, cell therapies have shown promise in treating osteoarthritis.

The high death rate of cartilage cells, termed chondrocytes, in osteoarthritic joints is a key process underlying cartilage loss. Thus, injecting chondrocytes directly into damaged joints can be beneficial. Autologous Chondrocyte Implantation (ACI), which uses laboratorygrown chondrocytes derived from the patients themselves, is now a common cellular therapy for osteoarthritis. Despite promising outcomes, this technique is not perfect. As these chondrocytes originate from the osteoarthritic joint, they do not function as well as healthy chondrocytes and thus fail to produce the high-quality cartilage needed. Further, only a small percentage of injected cells (<22%) survived and these cells do not readily multiply, which leaves the ultimate goal of replenishing the chondrocytes hard to achieve.

MSCs Stopping Osteoarthritis Progression | Rather than chondrocytes, mesenchymal stem cells (MSCs) have gained popularity as a new cellular therapy for osteoarthritis. MSCs are cells which can make copies of themselves and become specialised tissue cells such as fat cells, cartilage cells, or bone forming cells under the right stimuli. They are most commonly found in adult bone marrow and fat tissues.

Researchers have shown that injecting MSCs into osteoarthritic joints can relieve pain and improve joint function with very few side effects. It is thought that MSCs slow osteoarthritis progression through two main mechanisms. First, MSCs can turn into chondrocytes to compensate for chondrocyte loss. However, similar to the injection of chondrocytes, only a small proportion of injected MSCs survive and remain in the joints, and an even smaller percentage of these MSCs turn into chondrocytes, which means this mechanism contributes very little to stop disease progression. Therefore, most of the research in the past decade has focused on the second mechanism: the ability of MSCs to regulate immune response through secreted molecules.

In osteoarthritis, cartilage debris triggers the body's innate immune response and recruits immune cells into the joint to ‘clean up’ cartilage debris. These cells also secrete inflammatory mediators, such as cytokines and chemokines, to further aid the ‘cleaning’ process. However, these mediators sensitise chondrocytes to secrete more cartilage-degrading enzymes, which in turn enhance cartilage breaking down. This establishes a negative feedback loop within the joint, whereby losing cartilage leads to more cartilage breakdown and worsens disease severity. MSCs can break this loop through immunomodulation. Through secreted molecules or direct binding with immune cells, MSCs can reduce the secretion of inflammatory molecules and enhance the production of anti-inflammatory ones in those cells. In this way, MSCs reduce inflammation in the osteoarthritic joint and minimise cartilage loss and disease progression.

Resident MSCs In Osteoarthritis | MSCs can be found in both joint tissues and bone marrow, which can all be recruited to the joint cavity following joint injury. This raises the question of why native MSCs did not heroically stop the development of osteoarthritis in the first place. They may have tried but often become the accomplice of osteoarthritis! Compared to MSCs from healthy joints, MSCs in arthritic joints grow slower and are less likely to turn into chondrocytes. Researchers at the University of Leeds found that MSCs from patients with severe osteoarthritis have a higher expression of genes responsible for new bone formation, which means these MSCs tend to become boneforming cells. This means that native MSCs may facilitate osteophyte formation, a bony structure typically found in osteoarthritic joints. Osteophytes worsen the disease through narrowing the joint space and creating misalignment of bones.

You may wonder what determines the type of cells MSCs turn into. This largely depends on the chemical environment that MSCs are situated in. Key molecules such as vitamin C can trigger a series of downstream chemical reactions inside cells through switches on the cell surface. These reactions are termed signalling pathways. Studying these pathways may identify ways to manipulate MSC differentiation in arthritic joints.

Modified MSCs For Slowing Osteoarthritis

Progression | Scientists at John Hopkins University spotted a strong relationship between osteoarthritis development and a signalling factor named transforming growth factor beta (TGF- ) in MSCs. The activation of TGF- signalling along with bone-forming signalling transforms MSCs into osteoblasts. In a mouse model of osteoarthritis, abnormal bone formation closely correlates with increased TGFsignalling in MSCs. A further study showed that blocking the binding site of TGF- on the surface of MSCs led to a reduction in osteoarthritis symptoms in mice. In the future, it may be therapeutically useful to inject MSCs which lack TGF- receptors, as these are more likely to differentiate into chondrocytes and advance cartilage healing.

The duality of MSCs in either slowing or contributing to osteoarthritis means that clinicians need to carefully use them for therapy. By acquiring a deeper understanding of the disease and MSCs at a molecular level, researchers can make the most optimal treatment for millions of patients just like the old lady who lives next door with osteoarthritis

Minji Ai is a 2nd year PhD student in Biological Science at Darwin College. Artwork by Biliana Tchavdarova Todorova.