Research Project
10264052
OA is a major debilitating disease caused by the gradual loss of cartilage, primarily affecting the knees, hips, hands, feet, and spine. OA increases aggregate health care expenditures by $186 billion annually. The Centers for Disease Control and Prevention (CDC) estimates 27 million Americans suffer from OA. Estimates show that by year 2030, 20% of the adult U.S. population, or nearly 67 million people, will have physician-diagnosed arthritis. OA treatments focus on reducing inflammation and pain symptoms while joint degradation continues. The lack of repair mechanism will eventually lead to a condition that necessitates total knee replacement surgery. One of the major drawbacks of current therapeutics being developed is the potential to induce chondrocyte hypertrophy. Chondrocytes in OA cartilage show an aberrant hypertrophic phenotype and actively produce cartilage-degrading enzymes. Unfortunately, new treatments in development, such as recombinant BMP2, induce chondrocyte hypertrophy, further exasperating the problem. Therefore, although they are very potent in inducing ECM secretion and stimulating chondrogenesis, they are not useful for OA treatment. We propose the use of novel peptide CK2.1 to treat OA. CK2.1 is a mimetic peptide of the Bone Morphogenetic Protein receptor (BMPRIa). The peptide incorporates the phosphorylation site for Casein Kinase II (CK2) of the BMPRIa (SYED, AA475?479) and contains the Antennapedia Homeodomain signal sequence for cellular uptake. In our pilot study, we demonstrated that CK2.1 has the potential to induce ECM secretion and chondrogenesis without the induction of hypertrophy. We also demonstrated that CK2.1 repaired the cartilage in a DMM mouse model. We further conjugated CK2.1 to hydrogel particles to enable a sustained release of CK2.1 into the intra articular cavity releasing the peptide for multiple days. While results from our pilot study are promising, it is unclear if our novel peptide will induce chondrocyte hypertrophy in the long- term. Furthermore, it is unclear which cell population the peptide acts on, how far it diffuses into the cartilage, and what signaling pathways it activates. This proposal will answer these critical questions that must be answered before CK2.1 can be further developed. This proposal is high risk and also high reward. CK2.1 may be the first peptide that can regenerate cartilage without driving chondrocytes into apoptosis or osteoblasts. If this is the case our studies will revolutionize the clinical research.
