The many benefits of MSCs on bone flaws and cartilage damage

Skeletal diseases affect millions of people worldwide, especially older populations. Common disorders include fractures, osteoporosis, osteogenesis imperfecta, and osteoarthritis. These conditions can be caused by injury or chronic ailments, leading to bone density loss, deformities, and joint swelling and stiffness

Many current treatments aim to treat and protect bones from different disorders. Medications have been developed to help lower bone breakdown risk and protect against further fractures. Other therapies can help build new bone structures and strengthen bone in conditions like osteoporosis. While these treatments can be effective in enhancing bone and repairing some damage, they don’t address the root cause and are only minimally effective in regenerating bone structure.

In response to the need for more effective treatments for skeletal disease, stem cells are emerging as a promising therapeutic option. These young cells haven’t yet become a specific cell type, meaning they can be placed into any tissue to repair or replace cells of a disease.

The researchers of this article explore how different types of stem cells can have therapeutic benefits in different bone and cartilage conditions.

Structure: What bones are made of

Bones are the central part of the skeletal system, providing structural and functional use to the body. Without our skeleton, we would be a puddle of skin and organs on the floor. Our bones also help protect us, like the rib cage surrounding our lungs. They also make bone marrow, regulate our blood’s pH levels, and maintain calcium and phosphate balance.

The bone substance comprises compact (called cortical) and spongy (called cancellous) bone types. They have different mass-to-volume ratios, with cortical bone being denser and providing the bulk structural strength. On the other hand, the cancellous one is porous and less dense. It’s found mainly at the end of long bones and in the interior of the vertebrae, the bones that make
up the spine.

There are a variety of different cells that make up the bone structure.

Osteoprogenitors: Parent cells to osteoblasts; these are involved in bone formation.
Osteoblasts are bone-forming cells that create the materials that make up bone and help
them harden, a process known as mineralization.
Bone Lining Cells: Cover the surfaces of bones that are not undergoing remodeling or
changes.
Osteocytes: Mature osteoblasts set in the bone structure; they help maintain bone
tissue.
Osteoclasts: Large cells that reabsorb bone, playing a key role in bone remodeling and
calcium balance.

These cells comprise the bone matrix, a combination of organic and inorganic phases. The
bone matrix is a central part of the structure and provides structural support.

How MSCs can help with Bone diseases

Mesenchymal stem cells (MSCs), also known as Medicinal Signaling Cells, are a type of multipotent stem cell capable of transforming into various cell types. These cells come from different tissues, including bone marrow, adipose (fat), the umbilical cord, placenta, dental tissue, synovial (joint) fluid, foreskin, breast milk, and menstrual blood. We widely use MSCs to
repair and restore damaged or dying cells, produce beneficial substances like growth factors and anti-inflammatory cytokines, and regulate the immune system by calming natural killer cell activity. Research suggests MSCs significantly benefit repairing and regenerating tissues in various bone and cartilage-related conditions.

Intervertebral disc (IVD) degeneration

The discs in our spinal cord act as cushions between vertebrae, but they can deteriorate with age, injury, or overuse, reducing flexibility and movement in the neck and spine. While IVDs may contain regenerative cells similar to bone marrow MSCs (BM-MSCs), preclinical and clinical trials have demonstrated that MSCs are promising for regenerating diseased and damaged IVDs. Adipose-derived MSCs protect specialized cells in the center of IVD, called NP cells, by blocking the activity of caspase-9 and caspase-3. These are key enzymes in triggering, apoptosis, or cell death. They also reduce pro-inflammatory factors, which help prevent cell death and degeneration of NP cells. Using scaffolds to add structure, MSCs can become chondrocyte-like cells, aiding in cell regeneration. They can also decrease inflammatory markers, making their injection more tolerated and preventing cell death.

Osteoporosis

As we age, our bones naturally weaken; osteoporosis occurs when bones lose mineral density and become fragile, leading to an imbalance between bone formation and breakdown. Current treatments focus on stopping bones from weakening, but they often have side effects and limited effectiveness. MSCs from various sources have shown benefits in combating osteoporosis by promoting new bone formation and reducing inflammation. Preclinical studies have demonstrated that MSCs from the umbilical cord (UC-MSCs) can improve bone mass and reduce bone breakdown. Injecting UC-MSCs into osteoporotic rats increased the number of bone-forming cells (osteoblasts) and boosted the levels of TGF-β1 (helps with cell growth and repair) and Runx2 (essential for developing bone and cartilage). MSCs from adipose tissue retain their properties over time and can effectively regenerate bone structure. Clinical studies indicate that MSC therapy effectively reduces pain, improves bone density, and increases collagen bone markers by transforming into osteoblasts to form new bone and reducing osteoclasts responsible for bone breakdown

Osteogenesis imperfecta (OI)

OI is a genetic disorder caused by gene mutations that produce collagen type 1, essential for bone strength and structure. It results in bone deformities, bone density loss, frequent fractures, pain, and joint flexibility. OI treatment focuses on bone regeneration, replacing damaged bones with healthy ones, and reducing the cells responsible for bone breakdown. MSC therapy has been used in animal and clinical models, transforming MSCs into functional osteoblasts that create new bone. A study on a model of OI showed that human fetal blood MSCs increased the activity of bone-related genes, such as osteocalcin, osteoprotegerins (OPG), osterix (OSX), and BMP2. Multiple clinical studies have shown successful transplant of MSCs into bone tissues, leading to new bone cells and improved bone growth and health.

Bone fractures

Fractures are common bone injuries, especially in children and older adults. While they usually heal over time, some cases can lead to long-term pain and disability, affecting daily life. Healing bone is a complex process that involves three key steps: stimulating new bone growth (osteoinduction), guiding the growth (osteoconduction), and integrating new bone with existing bone (osteointegration). Traditional treatments include bone grafts and synthetic substances like calcium sulfate and calcium phosphate cement to enhance healing.

MSCs offer a promising alternative due to their ability to turn into different bone cells. They turn into osteoblasts, which help heal broken bones and reduce inflammation, aiding recovery. Scaffolds can further support MSCs by bonding to existing bone, increasing survival, migrating to damaged areas, and helping with bone remodeling and formation.

Cartilage disorders and cell therapy

The second principal component of the skeletal system is cartilage. This strong, connective tissue is found in the ears, nose, IVDs, joints, and ribs. It doesn’t have blood vessels, which can make it difficult to heal on its own. The most common ways cartilage is damaged are through trauma, age, chronic disease, and repetitive loading, leading to stress.

There are three types of cartilage:

Hyaline Cartilage: The most common type of cartilage found in joints, providing a smooth surface for movement and load transmission.
Elastic Cartilage: Found in areas like the ear, providing flexibility.
Fibrocartilage: Found in intervertebral discs and joint capsules, providing tensile strength and absorbing shock.
Because cartilage recovery is often surgery or managing pain, MSCs provide a potential approach to tissue repair.

Osteoarthritis (OA)

This common disorder causes degeneration in articular cartilage, subchondral bone, and bone spurs (osteophytes). Patients with OA can’t produce enough functional matrix to repair damaged cartilage, leading to joint pain, limited range of motion and mobility, stiffness, and swelling. It’s challenging to treat OA due to cartilage’s limited healing capacity. Overall, research findings showed that MSC-based therapy promotes pain alleviation and improves OA, mostly because of MSCs’ capacity for differentiation. Studies have shown that TGF-β1 and insulin-like growth factor 1 (IGF-1) help MSCs become cartilage cells. MSCs can create many new cells in a short amount of time while turning into cartilage-like cells (chondrocytes). This is in contrast to some that feel it’s the secretion from MSCs that do most of the healthing to cartilage. It’s likely a combination of differentiation and differentiation that explains the benefits. Overall, this regeneration improves function and reduces pain. Specifically, MSCs can create new collagen matrix, reduce inflammation, improve pain, and improve cartilage volume in knee OA. UC-MSCs are particularly promising as they can form new cartilage without the risk of forming bone in places where cartilage should be, a side effect of some other MSCs.

Rheumatoid arthritis (RA)

Another form of arthritis is Rheumatoid arthritis (RA), an inflammatory disease that affects the joints and causes cartilage and bone breakdown. The primary cause of RA is thought to come from cells in our immune system, our T and B Cells. Autoreactive B-cells contribute to the pathophysiology of the disease by producing autoantibodies, activating T cells, and producing pro-inflammatory cytokines. Studies showed that MSCs help trigger the death of activated T cells through the Fas ligand (FasL)/Fas signaling pathway in arthritis. MSCs may also influence B cells through activations, proliferation, survival and Breg induction. Thereby making these key cells in our immune system more advantageous for RA. MSCs have demonstrated benefits in regenerating cartilage, creating chondrocytes, and reducing pro-inflammatory molecules, which helps reduce inflammation. In some preclinical models, MSCs reduced joint swelling and cartilage destruction, and UC-MSCs prevented arthritis progression.

How MSCs work (regeneration properties)

Due to their versatile biological capabilities, MSCs play a crucial role in repairing and regenerating bone and cartilage tissues. Their ability to migrate to injury sites and differentiate into various cell types necessary for tissue repair makes them invaluable in regenerative medicine. MSCs also have the unique capacity to modulate inflammatory responses, which is critical in creating a conducive environment for healing. Furthermore, they promote angiogenesis, or the formation of new blood vessels, ensuring that the regenerating tissues receive adequate oxygen and nutrients. These multifaceted mechanisms highlight the potential of MSCs to revolutionize treatments for skeletal disorders and injuries.

How to choose the best MSCs

When choosing a source of mesenchymal stem cells (MSCs) for treatment, it’s important to consider the unique abilities of MSCs from different tissues. Each type of MSC works differently and has more helpful qualities for certain diseases. For example, bone marrow MSCs (BM-MSCs) are commonly used and are excellent for bone metabolism, homeostasis, and cell repair, but they secrete the fewest immune-related chemokines. Adipose-derived MSCs (AD-MSCs) have high Toll-like receptors (TLRs), which play a key role in the immune system and help reduce inflammation. Some of the most potent MSCs come from Wharton’s Jelly in the umbilical cord (WJ-MSCs). These cells have a higher ability to increase and produce more pro-inflammatory cytokines, growth factors, proteins for new blood vessels, extracellular matrix components like collagen, and matrix metalloproteinases (MMPs) essential for wound healing. There’s also the consideration of the viability and amount from each source. A cell’s viability measures the number of live and healthy cells in a population. As we age, we lose the amount of MSCs from bone marrow and adipose tissue. Additionally, these cells can be “older” and not perform as well. UC-MSCs are young and viable, have demonstrated remarkable regenerative abilities, and don’t need surgical procedures to obtain them from the patient since they come from safe cords.

Conclusion

The results from this study indicate the vast benefits MSCs have for supporting bone and cartilage disorders. The need for new treatments is essential as our older population continues to go and is at an increased risk of bone damage and age-related disorders. Learning about the different types of MSCs and their applications in bone and cartilage disorders unlocks significant therapeutic benefits. These cells enhance the repair and restoration of damaged tissues and produce essential growth factors and anti-inflammatory cytokines that promote healing. Using the unique properties of MSCs from various sources, we can develop more effective treatments for bone and cartilage disorders, leading to better patient recovery and quality of life.

Kangari, P., Talaei-Khozani, T., Razeghian-Jahromi, I. et al. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 11, 492 (2020).
https://doi.org/10.1186/s13287-020-02001-1