Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Dr. Frank Beier

Abstract

Osteoarthritis (OA) is a disease that gradually robs affected individuals of their mobility and places a substantial burden on health care systems and economies. OA results from pathological changes in bone, cartilage, synovium and supporting structures which are all essential to joint function. Cartilage degeneration, a hallmarking feature of OA, is an irreversible and untreatable consequence of these changes. Though the mechanisms underlying the initiation of cartilage breakdown remain unclear, joint injury and aging are risk factors. Pannexins (PANXs), a novel family of channel forming glycoproteins, have been suggested as important mediators of early OA. Therefore, my thesis tested the hypothesis that PANX1 and PANX3 promote cartilage breakdown in OA.

We began by generating novel Panx3 ‘floxed’ mice to investigate skeletal development and OA in vivo. Firstly, I found that global and cartilage specific Panx3 deletion was not associated with any obvious differences in skeletal development. I then compared OA development, following destabilization of the medial meniscus between WT mice and mice lacking Panx3 globally or specifically in cartilage. Histopathological assessment revealed that Panx3 deletion protected against surgically induced OA, highlighting a key role for PANX3 in promoting cartilage breakdown.

Using the same model as above, I compared the development of OA in WT and Panx1-/- mice. In this study, I show that unlike PANX3, global deletion of Panx1 is not associated with protection from cartilage damage following DMM. Panx1 deletion was however associated with the formation of smaller osteophytes than those in WT mice, suggesting a role for PANX1 in bone, but not cartilage pathology in surgically induced OA.

Finally, I examined the role of global Panx3 and Panx1/Panx3 deletion on skeletal health and OA development during aging. Interestingly, Panx3 and Panx1/Panx3 deletion was not associated with increased mortality or significant changes in body composition with age, however mCT analysis revealed small but significant reductions in the size of Panx3-/- mice Panx1-/-/Panx3-/- skeletons compared to WT. Furthermore, in contrast to above findings, both Panx3 and Panx1/Panx3 deletion accelerated cartilage breakdown with aging.

These data support a novel and unique, context dependent role for Panx3 and possibly Panx1 in osteoarthritis.

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Available for download on Friday, September 06, 2019

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