Studies at the University of California, San Diego have provided the first data implicating mitochondrial dysfunction in osteoarthritis. This collaboration recently received support from a research grant awarded by the Biotechnology Strategic Targets for Alliances in Research (BioSTAR) organization.
Mitochondria play a uniquely critical role in generating energy, in metabolism and in determining cell life and death. They also contain the only non-nuclear DNA in animal cells, so that knowledge of how the mitochondrial and nuclear genomes interact is crucial to the understanding of cellular function and dysfunction associated with disease pathology. Over 50 debilitating human diseases are known to be caused by well-characterized mitochondrial genetic mutations or functional abnormalities. By focusing on fundamental mitochondrial physiology and genomics, MitoKor, together with its large network of academic collaborators, has identified specific changes in mitochondrial function that are also associated with a number of widespread degenerative and metabolic diseases, including osteoarthritis. MitoKor is developing novel therapeutics to treat these late-onset diseases by treating the cell’s mitochondria.
Osteoarthritis is the leading cause of disability in the United States, affecting more than 16 million Americans over the age of 60. Most of the available therapies focus on moderating secondary inflammation, making non-steroidal anti-inflammatory drugs (NSAIDs), the most widely used of all drugs, despite potentially serious gastrointestinal and renal side effects. Recent introductions of cyclooxygenase 2 (COX-2) inhibitors have addressed some of the latter effects, but the available therapies have yet to address the underlying inability to maintain cartilage that leads to the joint deterioration that elicits inflammation.
Chondrocytes are connective tissue cells that fabricate and maintain the cartilage cushioning most joints. Because chondrocytes exist in isolated islands, surrounded by non-vascular cartilage, it has long been assumed that they made little use of mitochondrial respiration because it requires constant delivery of molecular oxygen from the circulatory system. However, studies performed at MitoKor and at the University of California, San Diego indicate that the integrity of articular cartilage is directly dependent on mitochondrial function in chondrocytes. For example, even modest inhibition of mitochondrial respiration, sufficient to repress chondrocyte ATP levels by 50%, results in almost complete blockage of proteoglycan and collagen synthesis needed to maintain and repair injured cartilage. These conditions also prevent the normal ability of transforming growth factor to increase excretion of inorganic phosphate, thereby worsening deposition of pathologic hydroxyapatite crystals. Importantly, nitric oxide (NO), produced by stressed chondrocytes and as part of the inflammatory response, very effectively inhibits chondrocyte mitochondrial function. Together, these studies indicate that chondrocyte mitochondrial dysfunction is an early event leading to cartilage disrepair that, in turn, elicits an inflammatory response. Once begun, inflammation further undermines mitochondrial function, thereby worsening cartilage repair.
The studies outlined here indicate that early-intervention strategies to improve chondrocyte mitochondrial function should moderate cartilage degradation, and correspondingly deter the ensuing inflammatory response. MitoKor’s MitoMetric™ screening programs have already yielded several novel compounds that improve mitochondrial function in cultured chondrocytes, and animal studies are underway. For example, MITO-4042 preserves the ability of chondrocytes to elaborate and repair cartilage under pro-inflammatory conditions that normalluy undermine chondrocyte function in osteoarthritis.
Mitophenome MitoMetric™ drug and target discovery strategy offers significant advantages over the “one molecule – one target” method of drug screening in that potential targets for a given molecule can be identified while defining the molecular pathway for the action of each compound class. This program, therefore, has the potential to accelerate the development of effective new therapeutic agents for osteoarthritis by:Dr. L Gevaert
Enabling rapid screening of compound libraries using proprietary functional assays that assess mitochondrial function.
Obviating the initial restriction that a known site of action be identified, thus facilitating the discovery of novel lead structures.
Providing the technology for rapid identification and validation of protein targets that mediate the protective activities of the novel chemical entities.