McSorley, E. | bioRxiv Science

bioRxiv2020

The ciliary protein IFT88 controls post-natal cartilage thickness and influences development of osteoarthritis.

Mechanical and biological cues drive cellular signalling in cartilage development, health, and disease. Proteins of the primary cilium, implicated in transduction of biophysiochemical signals, control cartilage formation during skeletal development, but their influence in post-natal cartilage remains unknown. Ift88fl/fl and AggrecanCreERT2 mice were crossed to create a cartilage-specific, inducible knockout mouse AggrecanCreERT2;Ift88fl/fl. Tibial articular cartilage (AC) thickness was assessed, through adolescence and adulthood, by histomorphometry and integrity by OARSI score. In situ mechanisms were investigated by immunohistochemistry (IHC), RNA scope and qPCR of micro-dissected cartilage. OA was induced by surgical destabilisation (DMM). Mice voluntarily exercised using wheels. Deletion of IFT88 resulted in progressive reductions in medial AC thickness during adolescence, and marked atrophy in adulthood. At 34 weeks of age, medial thickness was reduced from 104.00m, [100.30-110.50, 95% CI] in Ift88fl/fl to 89.42m [84.00-93.49, 95% CI] in AggrecanCreERT2;Ift88fl/fl (p<0.0001), associated with reductions in calcified cartilage. Occasionally, atrophy was associated with complete, spontaneous, medial cartilage degradation. Following DMM, AggrecanCreERT2;Ift88fl/fl mice had increased OA scores. Atrophy in mature AC was not associated with obvious increases in aggrecanase-mediated destruction or chondrocyte hypertrophy. Ift88 expression positively correlated with Tcf7l2, connective tissue growth factor (Ctgf) and Enpp1. RNA scope revealed increased hedgehog (Hh) signalling (Gli1), associated with reductions in Ift88, in AggrecanCreERT2;Ift88fl/fl cartilage. Wheel exercise restored both AC thickness and levels of Hh signalling in AggrecanCreERT2;Ift88fl/fl. Our results demonstrate that IFT88 is chondroprotective, regulating AC thickness, potentially by thresholding a Hh response to physiological loading that controls cartilage calcification.

molecular biology↗

bioRxiv2017

Individual differences in responsivity to social rewards: Insights from two eye-tracking tasks

Humans generally prefer social over nonsocial stimuli from an early age. Reduced preference for social rewards has been observed in individuals with autism spectrum conditions (ASC). This preference has typically been noted in separate tasks that measure orienting toward and engaging with social stimuli. In this experiment, we used two eye-tracking tasks to index both of these aspects of social preference in in 77 typical adults. We used two measures, global effect and preferential looking time. The global effect task measures saccadic deviation toward a social stimulus (related to orienting), while the preferential looking task records gaze duration bias toward social stimuli (relating to engaging). Social rewards were found to elicit greater saccadic deviation and greater gaze duration bias, suggesting that they have both greater salience and higher value compared to nonsocial rewards. Trait empathy was positively correlated with the measure of relative value of social rewards, but not with their salience. This study thus elucidates the relationship of empathy with social reward processing.

animal behavior and cognition↗