The goal of these studies is to expand and further characterize on our successful anti-inflammatory, antioxidant and silencing therapeutic treatments in - the MT-COMP mouse - our model of pseudoachondroplasia (PSACH). PSACH is a severe dwarfing condition characterized by marked disproportionate short stature, life long pain (starting in early childhood) and early onset osteoarthritis requiring joint replacements in young adulthood. There are no systematic treatments to reduce pain or to increase limb growth. We showed that mutations in cartilage oligomeric matrix protein (COMP) cause PSACH and, using the MT-COMP mouse demonstrated that mutant COMP is retained in the rER (rough endoplasmic reticulum) of growth plate chondrocytes where it stimulates the inappropriate and premature assembly of intracellular matrix, activating ER stress through CHOP signaling. We defined the pathologic downstream events of this ER stress, which involve widespread oxidative stress and inflammation throughout the growth plate, pathological processes that result in increased ER retention of COMP. The inflammatory process likely contributes to the severe early childhood joint pain in PSACH. This self-perpetuating feedback process ultimately causes pervasive apoptosis in chondrocytes throughout the growth plate. Our new and important findings show that continuous administration of anti-inflammatory or antioxidant agents from birth significantly reduces the chondrocytic stress response, decreases apoptosis and inflammation and importantly, results in longer bones. Moreover, we show that administration of COMP-antisense (ASO) from birth to P28 silences MT-COMP in growth plate chondrocytes by 68% and reduces the inflammatory process. This is important because COMP null mice are normal suggesting that knock down of COMP in growth plate chondrocytes would decrease the cellular burden of this disorder without having untoward health consequences. In this proposal, we will build on the power of our MT-COMP mouse model of PSACH to assess these novel and exciting interventions on long- term articular cartilage health, to define the temporal window(s)/dosages for postnatal treatment, to define the proteolytic pathways directed against MT-COMP that are enhanced by anti-inflammatory and antioxidant agents and to characterize ASO treatment MT-COMP growth plates. The significance of this work is high as we now have the potential to reduce pain and long-term morbidity, a significant problem in PSACH, with readily available therapeutic agents. Our findings are novel and based on our most recent data defining the natural history of PSACH at the cellular level in our mouse model. Therefore, we have arrived at a place in our research where we can refine and define anti-inflammatory, antioxidant and ASO therapies in mice, and the results can relatively easily be translated to humans in order to provide long-term improvement the lives of individuals with COMP mutations.
The goal of this grant is to continue testing our successful treatment approaches in our MT-COMP mouse that is a murine model of pseudoachondroplasia, a severe and debilitating dwarfing condition. We have defined the molecular mechanism by which mutant cartilage oligomeric matrix protein (COMP) causes the chondrocyte pathology and are using this information to apply treatments including anti-inflammatory, antioxidant and antisense oligonucleotide therapies. The outcome of these studies will have a significant impact on pseudoachondroplasia, other growth disorders and conditions involving ER stress.
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