Cartilage-Specific Knockout of the Mechanosensory Ion Channel TRPV4 Decreases Age-Related Osteoarthritis

Osteoarthritis (OA) is a progressive degenerative disease of articular cartilage and surrounding tissues, and is associated with both advanced age and joint injury. Biomechanical factors play a critical role in the onset and progression of OA, yet the mechanisms through which physiologic or pathologic mechanical signals are transduced into a cellular response are not well understood. Defining the role of mechanosensory pathways in cartilage during OA pathogenesis may yield novel strategies or targets for the treatment of OA. The transient receptor potential vanilloid 4 (TRPV4) ion channel transduces mechanical loading of articular cartilage via the generation of intracellular calcium ion transients. Using tissue-specific, inducible Trpv4 gene-targeted mice, we demonstrate that loss of TRPV4-mediated cartilage mechanotransduction in adulthood reduces the severity of aging-associated OA. However, loss of chondrocyte TRPV4 did not prevent OA development following destabilization of the medial meniscus (DMM). These results highlight potentially distinct roles of TRPV4-mediated cartilage mechanotransduction in age-related and post-traumatic OA, and point to a novel disease-modifying strategy to therapeutically target the TRPV4-mediated mechanotransduction pathway for the treatment of aging-associated OA

Cartilage-specific knockout of the mechanosensory ion channel TRPV4 decreases age-related osteoarthritis

Osteoarthritis (OA) is a progressive degenerative disease of articular cartilage and surrounding tissues, and is associated with both advanced age and joint injury. Biomechanical factors play a critical role in the onset and progression of OA, yet the mechanisms through which physiologic or pathologic mechanical signals are transduced into a cellular response are not well understood. Defining the role of mechanosensory pathways in cartilage during OA pathogenesis may yield novel strategies or targets for the treatment of OA. The transient receptor potential vanilloid 4 (TRPV4) ion channel transduces mechanical loading of articular cartilage via the generation of intracellular calcium ion transients. Using tissue-specific, inducible Trpv4 gene-targeted mice, we demonstrate that loss of TRPV4-mediated cartilage mechanotransduction in adulthood reduces the severity of aging-associated OA. However, loss of chondrocyte TRPV4 did not prevent OA development following destabilization of the medial meniscus (DMM). These results highlight potentially distinct roles of TRPV4-mediated cartilage mechanotransduction in age-related and post-traumatic OA, and point to a novel disease-modifying strategy to therapeutically target the TRPV4-mediated mechanotransduction pathway for the treatment of aging-associated OA

Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice

Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1−/− mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1−/− mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1+/+ mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1+/+ mice, but not in Col6a1−/− mice. Col6a1−/− mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1+/+mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1−/− mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data

Personal life satisfaction as a measure of societal happiness is an individualistic presumption: Evidence from fifty countries

Numerous studies document that societal happiness is correlated with individualism, but the nature of this phenomenon remains understudied. In the current paper, we address this gap and test the reasoning that individualism correlates with societal happiness because the most common measure of societal happiness (i.e., country-level aggregates of personal life satisfaction) is individualism-themed. With the data collected from 13,009 participants across fifty countries, we compare associations of four types of happiness (out of which three are more collectivism-themed than personal life satisfaction) with two different measures of individualism. We replicated previous findings by demonstrating that societal happiness measured as country-level aggregate of personal life satisfaction is correlated with individualism. Importantly though, we also found that the country-level aggregates of the collectivism-themed measures of happiness do not tend to be significantly correlated with individualism. Implications for happiness studies and for policy makers are signaled

Societal emotional environments and cross-cultural differences in life satisfaction: A forty-nine country study.

In this paper, we introduce the concept of ‘societal emotional environment’: the emotional climate of a society (operationalized as the degree to which positive and negative emotions are expressed in a society). Using data collected from 12,888 participants across 49 countries, we show how societal emotional environments vary across countries and cultural clusters, and we consider the potential importance of these differences for well-being. Multilevel analyses supported a ‘double-edged sword’ model of negative emotion expression, where expression of negative emotions predicted higher life satisfaction for the expresser but lower life satisfaction for society. In contrast, partial support was found for higher societal life satisfaction in positive societal emotional environments. Our study highlights the potential utility and importance of distinguishing between positive and negative emotion expression, and adopting both individual and societal perspectives in well-being research. Individual pathways to happiness may not necessarily promote the happiness of others

Introduction to a culturally sensitive measure of well-being: Combining life satisfaction and interdependent happiness across 49 different cultures

How can one conclude that well-being is higher in country A than country B, when wellbeing is being measured according to the way people in country A think about wellbeing? We address this issue by proposing a new culturally sensitive method to comparing societal levels of well-being. We support our reasoning with data on life satisfaction and interdependent happiness focusing on individual and family, collected mostly from students, across forty-nine countries. We demonstrate that the relative idealization of the two types of wellbeing varies across cultural contexts and are associated with culturally different models of selfhood. Furthermore, we show that rankings of societal well-being based on life satisfaction tend to underestimate the contribution from interdependent happiness. We introduce a new culturally sensitive method for calculating societal well-being, and examine its construct validity by testing for associations with the experience of emotions and with individualism-collectivism. This new culturally sensitive approach represents a slight, yet important improvement in measuring well-being

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely highpowered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP

Immunolabeling for collagen VI in the articular cartilage of the mouse tibial plateau cartilage.

<p>Top row: Collagen VI is found exclusively in the pericellular region of chondrocytes in the wild-type PCM (left). Bottom row: Corresponding DIC images overlaid with collagen VI labeling (green) and nuclear staining (red). Cartilage of the <i>Col6a1^−/−</i> mice (right) shows no labeling for collagen VI. Scale bar, 50 µm. WT = <i>Col6a1^+/+</i>; KO = <i>Col6a1^−/−</i>.</p

Histologic images revealed differences among wild-type and <i>Col6a1^−/−</i> knees at 2, 9, and 15 months.

<p>Coronal tissue slices (7 µm thick) were stained with fast green for collagen (blue) and safranin-O for proteoglycans (proteoglycans), and Harris' hematoxylin for nuclei (black). The left side is lateral while the right side is medial. The collagen VI null knees (right column) include a thick and proteoglycan-rich medial collateral ligament, increased chondrophyte formation on the lateral femur, larger trabeculae in both bones, and at 2 months a more confined growth-plate staining relative to the wild-type knees (left column). Scale bar = 1 mm. WT = <i>Col6a1^+/+</i>; KO = <i>Col6a1^−/−</i>.</p

MicroCT measures of trabecular bone structure.

<p>In the tibial epiphysis of collagen VI null mice (<i>Col6a1^−/−</i>), the structure model index (SMI, A) shows evidence of rod-like trabeculae from the earliest age, in contrast to the initially plate-like trabeculae of the wild-type mice. The trabecular bone volume (BV, B) is low from an early age and contributes to a higher bone tissue density (BD, D) in 2-month-old <i>Col6a1^−/−</i> mice. With increasing age, the <i>Col6a1^−/−</i> connectivity density (ConnDens, C) drops significantly at 15 months. Bars are mean ± SEM. Starred bars with no connecting lines are different from all other bars including each other. Horizontal lines connect statistically significantly different values. *<i>p</i><0.05; **<i>p</i><0.01. WT = <i>Col6a1^+/+</i>; KO = <i>Col6a1^−/−</i>.</p