by Beatrice Awasthi
figures by Aparna Nathan
Every day, our joints successfully bear huge amounts of force as we move about. For example, jogging and stumbling produce forces of up to 550% of a person’s body weight, respectively. Even walking generates forces as high as 480% of the body’s weight!
To successfully bear these massive forces without pain, joints must be healthy and intact. Deterioration of the joint can cause significant pain and greatly limit mobility. One of the most common causes of joint pain is degeneration of the cartilage in joints. In osteoarthritis, which affects over 300 million people worldwide, the joint becomes inflamed as the cartilage wears away, causing pain and consequent disability. Currently, osteoarthritis is considered incurable; treatment generally includes managing symptoms and slowing progression of the disease, culminating in surgery as a last resort. An ideal solution to salvage and repair the damaged joints would address both inflammation and cartilage damage. “Smart cartilage,” developed by scientists at Washington University in St. Louis and Duke University, is a promising solution with the potential to do exactly that.
How osteoarthritis develops
A joint is any area of the body in which bones come together, such as the elbows, knees, shoulders and hips. In healthy joints, a flexible connective tissue called cartilage coats the ends of the bones, so joints can move with minimal friction and the bones are protected from mechanical stress. Cartilage is composed of cells called chondrocytes that are surrounded by a network of molecules and minerals called the extracellular matrix. This matrix helps to protect the chondrocytes and preserve cartilage integrity (Figure 1).
Chondrocytes are naturally able to respond to mechanical signals because they have receptors that open in response to force (mechanoreceptors). When external forces stimulate these mechanoreceptors, internal signals within the chondrocytes trigger a process of cartilage building and repair, during which chondrocytes release specialized enzymes that degrade the existing cartilage as well as new matrix components to replenish and rebuild the tissue.
In osteoarthritis, the healthy balance between cartilage breakdown and repair is disrupted as signaling within chondrocytes stimulates them to primarily break down cartilage tissue (Figure 2). Chondrocytes then release signals that cause inflammation in the joint, which further breaks down cartilage. Eventually, the bone itself is damaged. Pieces of the joint components can sometimes break off and float around the joint, heightening inflammation. In severe cases, the destruction is such that bone-on-bone contact occurs (Figure 2). The inflammation and lack of cushion between bones can be excruciatingly painful and make it difficult to move a joint at all.
Smart cartilage as a new innovative treatment for osteoarthritis
While remaining physically active can encourage healthy tissue maintenance and taking anti-inflammatory medications can help with pain, osteoarthritis is considered irreversible. The effectiveness of anti-inflammatory medications in osteoarthritis may be limited by their ability to concentrate in osteoarthritic joints at sufficient doses to combat inflammatory signaling. For example, interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein marketed as the biologic drug Anakinra, is used to treat rheumatoid arthritis but is ineffective in treating osteoarthritis when injected into an osteoarthritic joint at conventional doses. Implants with the ability to adapt in response to the joint environment —known as smart implants— can augment the effect of anti-inflammatory drugs and might solve this issue.
Recently, scientists at Washington University in St. Louis and Duke University—led by first authors Robert Nims and Lara Pferdehirt—published their invention of smart cartilage, a development with exciting implications for osteoarthritis treatment. Their smart cartilage is made up of pig chondrocytes and has been engineered to produce IL-1Ra after mechanical forces and inflammatory signaling in a dose-dependent manner. Smart cartilage could overcome the dosage limitations of traditional anti-inflammatory drug administration by enabling the controlled release of the anti-inflammatory drug directly within an inflammatory joint setting in response to naturally occurring mechanical stimuli.
To create this smart cartilage, the scientists took advantage of an ion channel called TRPV4. TRPV4 senses the changes in the cartilage environment due to mechanical stress, and then signals to increase the production of certain proteins involved in cartilage remodeling and inflammatory signaling (Figure 3, left). Here, the scientists artificially replaced these original targets of TRPV4 with the anti-inflammatory IL-1Ra. Therefore, the resulting engineered chondrocytes, grown in dishes, produce the anti-inflammatory IL-1Ra when the TRPV4 senses changes in the cartilage environment like mechanical stimuli as well as inflammatory signals (Figure 3, right). While normal cartilage deteriorated when exposed to inflammatory signals in the dishes, chondrocytes engineered to produce IL-1Ra protected the cartilage when mechanically stimulated and exposed to the same inflammatory signals.
Implications of smart cartilage
Endowing chondrocytes with the ability to respond to mechanical stress within a pro-inflammatory environment has intriguing implications for the future. Engineering these cells to release anti-inflammatory factors in response to triggers of damage can address the debilitating inflammation in joints affected by osteoarthritis in a localized manner, which could increase the effectiveness of anti-inflammatory medications. Future tests are necessary to evaluate the engineered cartilage in living organisms (in vivo), since all of the experiments performed with it thus far were in dishes (in vitro).
Additionally, this work holds a lot of promise for cartilage implants in the future. Cartilage implants, in which chondrocytes removed from a patient are grown in a lab and reimplanted into the patient, are a desirable surgical treatment option for osteoarthritis due to their ability to repair damage while preserving a patient’s natural joint and joint mobility. The success of implants is sometimes limited because the chondrocytes might be unable to thrive following implantation. Smart cartilage could be further engineered to better adapt to different joint environments following implantation. Such adaptability of the engineered chondrocytes could improve the success rates of such cartilage implants. More generally the creation of smart cartilage opens the door for the innovation of other “smart” tissue systems that can be tailored, on the molecular level, to address various diseases.
Beatrice Awasthi is a third-year PhD student in the Biological and Biomedical Sciences program at Harvard University, where she studies signaling in colon cancer.
Aparna Nathan is a fourth-year Ph.D. student in the Bioinformatics and Integrative Genomics Ph.D. program at Harvard University. You can find her on Twitter as @aparnanathan.
For More Information:
- Many patients suffering from osteoarthritis can manage their pain using non-surgical treatments.
- Extensive work is being done to develop regenerative approaches that harness the body’s own healing process to treat osteoarthritis.
- The creation of smart biomaterials is an innovative area of research that has the potential to be used in treating myriad diseases, but involves important considerations.
- Several different models are currently used to study osteoarthritis.