| Popis: |
Osteoarthritis (OA) is the most common joint disease and a major cause of physical disability, however no disease modifying treatments are available. To better understand the molecular mechanisms involved, my colleagues previously performed microarray studies on a surgical rodent model of OA. Transforming growth factor alpha (TGFa) was identified as a novel growth factor involved in cartilage degeneration and subsequent experiments revealed that it induced an OA-like phenotype in articular chondrocytes. These findings lead to the overarching hypothesis for my thesis: TGFa promotes OA. I began by studying TGFa’s interaction with endothelin receptor A (ET(A)R) as this signaling system is known to be involved in both aging and OA. I used in vitro cultures to examine whether TGFa-effects were regulated by this pathway and found that TGFa induced expression of ET(A)R at both the gene and protein level. By inhibiting ET(A)R I was able to partially block some deleterious TGFa effects, however, it was evident that additional downstream targets were involved in TGFa signaling. To examine the role of TGFa in vivo, I used the Tgfa null mouse. I first examined bone development as developmental events are often recapitulated in disease. Tgfa null mice had a transient growth plate phenotype characterized by an expanded hypertrophic zone and a delay in the transition from cartilage to bone. I also observed a decrease in RANKL and MMP13 gene expression as well as fewer osteoclasts as the cartilage/bone junction. These data suggest that decreased matrix resorption is responsible for the persistence of the hypertrophic zone. Lastly, I examined post-traumatic and aging models OA. Interestingly, I found that young adult Tgfa null mice were protected from developing OA in the traumatic model, however they were not protected with age. These data suggest that TGFa might be more relevant as a therapeutic target in post-traumatic subtypes of OA but not necessarily in idiopathic disease. Overall, these data demonstrate a novel role for TGFa in both bone development and OA. My developmental and disease data support my hypothesis, as TGFa appears to be a major regulator of cartilage catabolism in both systems. |
