Kartogenin and its effects on the OA synovial joint

According to the Center for Disease Control (CDC), osteoarthritis (OA) effects over 32.5 million adults in the U.S. alone, making it the most common form of arthritis. OA is a disease of the synovial joints and involves a breakdown of the cartilage, the synovial fluid, and modification of the underlying bone. Over time, pain in the effected joints increases as does stiffness resulting in progressive loss of motion. Swelling also occurs and increases in some people to the point where work or even daily tasks become difficult to impossible. What if there was a way to stop, and even reverse the effects of this debilitating disease? What if it didn’t involve stem cell transplants and was being tested in humans today?

The Structure and Function of the Synovial Joint

A synovial joint is one in which a fluid filled cavity exists between the bones of the joint. The synovium or synovial membrane is bounded by specialized cartilage and the cavity it surrounds contains a special fluid. This Synovial fluid is vitally important for healthy joint function as it absorbs the impact of shocks between the bones as well as providing lubrication for the joint as well as performing several other important functions.

1OpenStax College / CC BY (https://creativecommons.org/licenses/by/3.0)

The cells that make up the synovial membrane, synoviocytes, produce the synovial fluid, but they also nourish and produce proteins that regulate the articulating cartilage that covers the ends of the bones of the joint. Also known as hyaline cartilage, it further reduces the impact of shocks as well as providing lubrication between the bones.

The hyaline cartilage is composed of what is known as the extracellular matrix that is comprised by collagen and water. The cells of the cartilage are called chondrocyte and they produce and maintain the extracellular matrix. There are no blood vessels, nerves, or lymphatics; the vessels of the immune system. Water makes up about 80% of the cartilage in some places and distributes nutrients as blood vessels would in the other tissues of the body. Pressure on the joint from various sources such as walking moves the water through the cartilage. ¹

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Chondrocytes are highly specialized cells that are responsible for the development, maintenance, and repair of the dense matrix that gives structure to the cartilage. The structure of the cartilage is the result of interactions with complex molecules produced by the chondrocytes.¹ Inflammation of the surrounding tissues has a negative effect on their ability to produce those molecules. ²

Chondrocytes rarely communicate with other cells like most cell types do. They respond instead to changes in the amount of pressure around them, the force of gravity for example, and signals from the extracellular matrix. Also unlike other cell types they do not replicate often, and their survival depends on the health of the synovium and the optimum chemical composition of their surroundings.¹

Osteoarthritis in the Synovial Joint

Since chondrocytes are responsible for the repair of damage to the cartilage and even in healthy joints they don’t replicate often, the potential for repair of the cartilage of synovial joints is low.¹ Osteoarthritis is thought to be caused by damage to the articulating cartilage from a number of sources ranging from repetitive movements to injury. The root of Osteoarthritis is the inability of the chondrocytes to maintain healthy breakdown and growth of the extracellular matrix.³

Some degree of wear in cartilage and bone is normal in healthy joints.  This wear results in the production of what are known as “wear particles” that migrate into the synovium and are found in the synovial fluid.  Normally, these particles are cleared away by immune system cells called macrophages.  However, when high concentrations exist in the synovial fluid it overwhelms the ability of the macrophages to clear them.  The particles remain in the synovial fluid where they can interact with the synoviocytes that make up the synovial membrane containing the fluid.⁴

This interaction can cause synoviocytes to produce signaling molecules that are received by chondrocytes causing chondropathy; the degradation of the articulating cartilage as is seen in osteoarthritis. The overwhelmed macrophages also release signaling molecules which, together with the molecules from the synoviocytes, cause inflammation in the surrounding tissue and signal the chondrocytes to further degrade the cartilage.  A further effect of this signaling is a decrease in the number of chondrocytes themselves. ⁵

In osteoarthritis and other conditions, chondropathy begins with a softening of the layer of cartilage closest to the synovium along with the development of fissures.  As the disease progresses the cartilage continues to thin until it is eventually completely destroyed.³  This leaves only the rigid calcified cartilage of the underlying bone, rather than the absorbent articular cartilage, to absorb shocks encountered in normal activity.

After or possibly during chondropathy, the bone itself begins to change. In some locations bone is broken down where in others new bone is grown. These new bone growths, called osteophytes, can be a source of pain in the osteoarthritic joint. Bone loss and loosening of the tendons can cause joint deformity.

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Reversing Osteoarthritis

Removing Debris from the Synovium

Given the effects of the wear particles on the cells of the synovial membrane, clearing the synovium of these particles would seem important in any effort to alleviate the pain and stop cartilage degradation. There have been many clinical trials in which a saline solution was used to “wash” the joint. Many of these used a drug such as a cortical steroid combined with a saline solution in test patients. The control group, those who do not get the drug being tested, received a saline solution without the drug.

When a large number of these clinical trials focused on osteoarthritis in the knee were reviewed it was found that washing the joint, also known as tidal irrigation or lavage, is an effective treatment for the pain in osteoarthritic joints.⁶ While the review focused on the analgesic effects of saline as an explanation of the effectiveness of the irrigation, the long term pain reduction may actually be the result of the clearing of the wear particles from the synovium.⁷

Kartogenin

The research shows that the wear particles that may play a role in the onset of Osteoarthritis. They contribute to the pain and articular cartilage destruction, but relief can be obtained by tidal irrigation. But what about the cartilage that has already been destroyed? To reverse the effects of Osteoarthritis, that cartilage has to be regenerated, and for that chondrocytes are required.

In 2012 a team of researchers at Novartis experimented with 22,000 different molecules in an effort to induce stem cells present in synovial joints to become chondrocytes. All of them were similar to natural signaling molecules that are found in stem cell maintenance and eventually, they found one, Kartogenin.⁸

During in vitro testing, testing done outside a living organism like in a test tube or petri dish, they found that Kartogenin induced stem cells to become chondrocytes. Even more important is that they found a type of collagen and a sugary protein called aggrecan expressed only in hyaline cartilage as well. The testing also showed cartilage hyperplasia, too much new cartilage, was not expected and that Kartogenin protected the chondrocytes from damage from the proteins produced by inflamed tissue.⁸

Kartogenin in Animal Studies

A requisite step in taking a molecule from the lab to becoming a new drug for humans is to first determine the safety and efficacy of the drug in animals. The Novartis team moved on to in vivo testing, testing in living organisms, using mice. Some of the mice in the testing had osteoarthritis like that resulting from overuse of a joint and others like that from a significant injury. After injecting Kartogenin into the affected joints, the team not only found cartilage regrowth, but also a reduction in wear particles. They also noted that only trace amounts of Kartogenin in the blood of the test subjects, not enough to cause side effects.⁸

Another study involved rabbits that had defects in the knees that ran the full depth of the cartilage. They were treated with Kartogenin and then examined at four and twelve weeks after treatment. At four weeks half of the cartilage had regrown and at twelve weeks they found that the cartilage had completely regrown. When they examined the cells of the new cartilage, they found it was normal hyaline cartilage and even the underlying bone had been reconstructed.

Kartogenin Today

The last step to making a drug available for prescription is testing for its safety, dosage levels, and efficacy in humans. This is done using clinical trials that generally take a few years to complete. They are broken down into five phases, numbered from zero (0) to four (IV) with phase four involving the drug being administered to hundreds or thousands of people after it has been shown to be safe and effective. Phases 0 and I include only a few people and are largely used to determine the safety and proper dosing of the drug. In Phase II trials a larger number of people are included and focuses more on the efficacy of the drug while still ensuring the safety of its use.

There is an ongoing Phase I clinical trial of Kartogenin that began in 2018 with a target enrollment of 60 patients. It started with 16 patients and an encouraging sign regarding safety is that enrollment of new patients accelerated to reach full enrollment by its conclusion in April of 2020. The pandemic has caused the interruption of more than 1,000 ongoing clinical trials as of May 2020. While some large pharmas have restarted recruitment, many studies remain on hold. The results of the Kartogenin’s clinical trial have yet to be released, but given that it completed with full enrollment raises the hope that Phase II trials are in the works.

1. Sophia Fox, A. J., Bedi, A. & Rodeo, S. A. The basic science of articular cartilage: structure, composition, and function. Sports Health 1, 461–8 (2009).

2. Terkeltaub, R., Yang, B., Lotz, M. & Liu-Bryan, R. Chondrocyte AMP-activated protein kinase activity suppresses matrix degradation responses to proinflammatory cytokines interleukin-1β and tumor necrosis factor α. Arthritis Rheum. 63, 1928–1937 (2011).

3. Man, G. S. & Mologhianu, G. Osteoarthritis pathogenesis – a complex process that involves the entire joint. Journal of medicine and life vol. 7 37–41 (2014).

4. Silverstein, A. M. et al. Toward understanding the role of cartilage particulates in synovial inflammation. Osteoarthr. Cartil. 25, 1353–1361 (2017).

5. Estell, E. G. et al. Cartilage Wear Particles Induce an Inflammatory Response Similar to Cytokines in Human Fibroblast-Like Synoviocytes. J. Orthop. Res. 37, 1979–1987 (2019).

6. Bar-Or, D., Rael, L. T. & Brody, E. N. Use of Saline as a Placebo in Intra-articular Injections in Osteoarthritis: Potential Contributions to Nociceptive Pain Relief. Open Rheumatol. J. 11, 16–22 (2017).

7. Robertson-Plouch, C. et al. A randomized clinical efficacy study targeting mPGES1 or EP4 in dogs with spontaneous osteoarthritis. Sci. Transl. Med. 11, (2019).

8. Bhatti, F.-U.-R. Kartogenin Induced Chondrogenesis of Stem Cells and Cartilage Repair. Int. J. Stem cell Res. Ther. 3, (2016).