EVIDENCE FOR MECHANICAL STRAINS INFLUENCE IN OSTEOPHYTE DEVELOPMENT

Purpose: Osteophytes are osteo-cartilaginous metaplastic tissue outgrowths of bone capped by cartilage usually found in degenerative and inflammatory joint disease. The presence and degree of maturity of osteophytes, along with joint space narrowing, are the main radiographic criteria for diagnosis and grading osteoarthritis (OA). Although osteophytes are known for being anatomic signs of advanced OA, they can occur in non-symptomatic joints, in joints with no other observable alterations, and in early stage OA. It remains unclear if they develop from molecular, physiological and/or mechanical stimuli. We hypothesized that mechanical strains play a role in osteophyte development. The overall objective of this thesis was to find evidence that osteophytes are influenced by mechanical strains. Methods: The first project was to develop a mechanically-induced osteophyte animal model. One single impact load that was reported to induce moderate joint damage was applied to the periosteum of the rat knee. Animals were sacrificed at four time points to characterize the evolution of damaged tissue and the joint by histology. A second study using human mature hip osteophytes was conducted to evaluate if mature osteophyte presented histological signs of proliferating and developmental processes. The histological characterization of mature osteophyte was used to compare findings of the mechanically-induced osteophyte in the animal model to validate the use of this rodent model in studying some aspect of osteophyte development of human. Lastly, a detailed three-dimensional (3D) radiological morphometric analysis was performed on microscopic computed tomography (µCT) scanned femoral heads collected from total hip arthroplasty patients presenting mature hip osteophytes. Quantitative morphometric measures of osteophytes internal structure was compared to three regions of the femoral head of known quality of organisation and mechanical constraint. Results and Conclusion: Osteophyte can be mechanically induced by a single load impact to the joint periosteum, indicating that a moderate trauma to the periosteal layer of the joint may play a role in osteophyte development. Mature osteophytes have proliferation, developing and remodelling zones and have trabecular structures. Mechanically-induced osteophytes and mature osteophytes presented similar histological composition. Mature osteophytes have organized internal structure. These results provide evidence that mechanical strain can influence osteophyte development.

Countermanding in rats as a practical model for investigation of adaptive control of behaviour, lifespan changes in behavioural control and neurotransmitter function

The countermanding paradigm was designed to investigate the ability to cancel a prepotent response when a stop signal is presented and allows estimation of the stop signal response time (SSRT), an otherwise unobservable behaviour. Humans exhibit adaptive control of behaviour in the countermanding task, proactively lengthening response time (RT) in expectation of stopping and reactively lengthening RT following stop trials or errors. Human performance changes throughout the lifespan, with longer RT, SSRT and greater emphasis on post-error slowing reported for older compared to younger adults. Inhibition in the task has generally been improved by drugs that increase extracellular norepinephrine. The current thesis examined a novel choice response countermanding task in rats to explore whether rodent countermanding performance is a suitable model for the study of adaptive control of behaviour, lifespan changes in behavioural control and the role of neurotransmitters in these behaviours. Rats reactively adjusted RT in the countermanding task, shortening RT after consecutive correct go trials and lengthening RT following non-cancelled, but not cancelled stop trials, in sessions with a 10 s, but not a 1 s post-error timeout interval. Rats proactively lengthened RT in countermanding task sessions compared to go trial-only sessions. Together, these findings suggest that rats strategically lengthened RT in the countermanding task to improve accuracy and avoid longer, unrewarded timeout intervals. Next, rats exhibited longer RT and relatively conserved post-error slowing, but no significant change in SSRT when tested at 12, compared to 7 months of age, suggesting that rats exhibit changes in countermanding task performance with aging similar to those observed in humans. Finally, acute administration of yohimbine (1.25, 2.5 mg/kg) and d-amphetamine (0.25, 0.5 mg/kg), which putatively increase extracellular norepinephrine and dopamine respectively, resulted in RT shortening, baseline-dependent effects on SSRT, and attenuated adaptive RT adjustments in rats in the case of d-amphetamine. These findings suggest that dopamine and norepinephrine encouraged motivated, reward-seeking behaviour and supported inhibitory control in an inverted-U-like fashion. Taken together, these observations validate the rat countermanding task for further study of the neural correlates and neurotransmitters mediating adaptive control of behaviour and lifespan changes in behavioural control.