Of Mice and Men

Non-muscle myosin II has diverse functions in cell contractility, morphology, cytokinesis and migration. Mammalian cells have three isoforms of non-muscle myosin II, termed IIA, IIB and IIC, encoded by three different genes. These isoforms share considerable homology and some overlapping functions, yet they exhibit differences in enzymatic properties, subcellular localization, molecular interaction and tissue distribution 1-6. Our studies have focused on the IIA isoform, and they reveal unique regulatory roles in cell-cell adhesion and cell migration that are associated with cross-talk of the actomyosin system with microtubules. In humans, various mutations in the MYH9 gene that encodes the myosin IIA heavy chain cause autosomal dominant disease, whereas in mice, the complete deficiency is embryonic lethal but heterozygous mice are nearly normal. We discuss here the differences between mouse and human phenotypes and how the wealth of mechanistic knowledge about myosin II based on in vitro studies and mouse models can help us understand the molecular and cellular pathophysiology of myosin IIA deficiency in humans.     

Deficiency of Thrombospondin-4 in Mice Does Not Affect Skeletal Growth or Bone Mass Acquisition,but Causes a Transient Reduction of Articular Cartilage Thickness

Although articular cartilage degeneration represents a major public health problem, the underlying molecular mechanisms are still poorly characterized. We have previously utilized genome-wide expression analysis to identify specific markers of porcine articular cartilage, one of them being Thrombospondin-4 (Thbs4). In the present study we analyzed Thbs4 expression in mice, thereby confirming its predominant expression in articular cartilage, but also identifying expression in other tissues, including bone. To study the role of Thbs4 in skeletal development and integrity we took advantage of a Thbs4-deficient mouse model that was analyzed by undecalcified bone histology. We found that Thbs4-deficient mice do not display phenotypic differences towards wildtype littermates in terms of skeletal growth or bone mass acquisition. Since Thbs4 has previously been found over-expressed in bones of Phex-deficient Hyp mice, we additionally generated Thbs4-deficient Hyp mice, but failed to detect phenotypic differences towards Hyp littermates. With respect to articular cartilage we found that Thbs4-deficient mice display transient thinning of articular cartilage, suggesting a protective role of Thbs4 for joint integrity. Gene expression analysis using porcine primary cells revealed that Thbs4 is not expressed by synovial fibroblasts and that it represents the only member of the Thbs gene family with specific expression in articular, but not in growth plate chondrocytes. In an attempt to identify specific molecular effects of Thbs4 we treated porcine articular chondrocytes with human THBS4 in the absence or presence of conditioned medium from porcine synovial fibroblasts. Here we did not observe a significant influence of THBS4 on proliferation, metabolic activity, apoptosis or gene expression, suggesting that it does not act as a signaling molecule. Taken together, our data demonstrate that Thbs4 is highly expressed in articular chondrocytes, where its presence in the extracellular matrix is required for articular cartilage integrity.     

Hair Toxic Element Content in Adult Men and Women in Relation to Body Mass Index

The primary objective of the current study was to estimate the hair toxic metal content in adults in relation to body mass index. A total of 1,229 persons including 719 women and 510 men were examined. All subjects were divided into two age groups: 1 and 2 periods of adulthood. All men and women were also subdivided into groups in relation to their values of body mass index (BMI): underweight, normal weight, overweight and obese. Hair aluminium (Al), beryllium (Be), cadmium (Cd), mercury (Hg), lead (Pb) and tin (Sn) content was evaluated using mass spectrometry with inductively coupled plasma. It has been shown that increase in body weight is accompanied by elevated hair cadmium content in women. At the same time, no significant alteration of hair cadmium concentration was observed in males. Higher values of scalp hair mercury and lead content were observed in men and women with increased body mass index independently of their age. BMI-related elevation of hair tin content was registered only in men of the first period of adulthood. A significant correlation between hair metal content and the values of BMI was observed for mercury independently of the gender of the subjects, whereas BMI values correlated significantly with hair cadmium levels in women and lead and tin levels in men. It has been also estimated that hair cadmium, mercury and lead levels in men exceed the respective values in women.     

Perceived Stress and Coping Strategies in Relation to Body Mass Index: Cross-Sectional Study of 12,045 Japanese Men and Women

BackgroundAccumulated evidence suggests a weak positive relationship between psychosocial stress and body mass index (BMI), but little is known about stress coping strategies and BMI.ObjectiveWe aimed to examine if perceived stress and coping strategies are related to BMI, with any of their mutual interactions on BMI.MethodsThis cross-sectional study included 5,063 men and 6,982 women aged 40-69 years. A self-administered questionnaire ascertained perceived stress and 5 items of coping strategies (emotion expression, emotional support seeking, positive reappraisal, problem solving, and disengagement). Analyses were performed by gender with adjustment for age, socioeconomic status, and lifestyle factors.ResultsNo significant associations were detected between perceived stress and BMI in either men (P_trend = 0.09) or women (P_trend = 0.58). In men, however, ‘disengagement’ showed an inverse association with BMI (P_trend < 0.001), and ‘positive reappraisal’ and ‘problem solving’ revealed a positive association with BMI (P_trend = 0.04 and 0.007, respectively) even after controlling for perceived stress. A possible interaction between perceived stress and ‘disengagement’ on BMI was found in men (P_interaction = 0.027); the inverse association between ‘disengagement’ and BMI was more evident in higher levels of stress (β = −0.13, P_trend = 0.21 in low; β = −0.22, P_trend = 0.01 in medium; and β = −0.24, P_trend = 0.06 in high). In men, ‘disengagement’ was inversely associated with overweight/obesity (odds ratio 0.79, 95% confidential interval 0.67-0.95), and “positive reappraisal” was positively associated with it (1.25, 1.02-1.54).ConclusionsCoping strategies may have an important role in developing overweight/obesity, particularly in men.     

Aged-Related Changes in Body Composition and Association between Body Composition with Bone Mass Density by Body Mass Index in Chinese Han Men over 50-year-old

Objectives

Aging, body composition, and body mass index (BMI) are important factors in bone mineral density (BMD). Although several studies have investigated the various parameters and factors that differentially influence BMD, the results have been inconsistent. Thus, the primary goal of the present study was to further characterize the relationships of aging, body composition parameters, and BMI with BMD in Chinese Han males older than 50 years.

Methods

The present study was a retrospective analysis of the body composition, BMI, and BMD of 358 Chinese male outpatients between 50 and 89 years of age that were recruited from our hospital between 2009 and 2011. Qualified subjects were stratified according to age and BMI as follows: 50–59 (n = 35), 60–69 (n = 123), 70–79 (n = 93), and 80–89 (n = 107) years of age and low weight (BMI: < 20 kg/m²; n = 21), medium weight (20 ≤ BMI < 24 kg/m²; n = 118), overweight (24 ≤ BMI < 28 kg/m²; n = 178), and obese (BMI ≥ 28 kg/m²; n = 41). Dual-energy X-ray absorptiometry (DEXA) was used to assess bone mineral content (BMC), lean mass (LM), fat mass (FM), fat-free mass (FFM), lumbar spine (L1-L4) BMD, femoral neck BMD, and total hip BMD. Additionally, the FM index (FMI; FM/height²), LM index (LMI; LM/height²), FFM index (FFMI; [BMC+LM]/height²), percentage of BMC (%BMC; BMC/[BMC+FM+LM] × 100%), percentage of FM (%FM; FM/[BMC+FM+LM] × 100%), and percentage of LM (%LM; LM/(BMC+FM+LM) × 100%) were calculated. Osteopenia or osteoporosis was identified using the criteria and T-score of the World Health Organization.

Results

Although there were no significant differences in BMI among the age groups, there was a significant decline in height and weight according to age (p < 0.0001 and p = 0.0002, respectively). The LMI and FFMI also declined with age (both p < 0.0001) whereas the FMI exhibited a significant increase that peaked in the 80-89-years group (p = 0.0145). Although the absolute values of BMC and LM declined with age (p = 0.0031 and p < 0.0001, respectively), there was no significant difference in FM. In terms of body composition, there were no significant differences in %BMC but there was an increase in %FM (p < 0.0001) and a decrease in %LM (p < 0.0001) with age. The femoral neck and total hip BMD significantly declined with age (p < 0.0001 and p = 0.0027, respectively) but there were no differences in L1-L4. BMD increased at all sites (all p < 0.01) as BMI increased but there were declines in the detection rates of osteoporosis and osteopenia (both p < 0.001). A logistic regression revealed that when the medium weight group was given a BMI value of 1, a decline in BMI was an independent risk factor of osteoporosis or osteopenia, while an increase in BMI was a protective factor for BMD. At the same time, BMD in L1-L4 exhibited a significant positive association with FMI (p = 0.0003) and the femoral neck and total hip BMDs had significant positive associations with FFMI and LMI, respectively (both p < 0.0001).

Conclusions

These data indicate that LMI and FFMI exhibited significant negative associations with aging in Chinese Han males older than 50 years, whereas FMI had a positive association. BMD in the femoral neck and total hip declined with age but an increased BMI was protective for BMD. LMI and FFMI were protective for BMD in the femoral neck and total hip.     

Sclerostin Immunoreactivity Increases in Cortical Bone Osteocytes and Decreases in Articular Cartilage Chondrocytes in Aging Mice

Sclerostin is a 24-kDa secreted glycoprotein that has been identified as a negative modulator of new bone formation and may play a major role in age-related decline in skeletal function. Although serum levels of sclerostin markedly increase with age, relatively little is known about whether cells in the skeleton change their expression of sclerostin with aging. Using immunohistochemistry and confocal microscopy, we explored sclerostin immunoreactivity (sclerostin-IR) in the femurs of 4-, 9-, and 24-month-old adult C3H/HeJ male mice. In the femur, the only two cell types that expressed detectable levels of sclerostin-IR were bone osteocytes and articular cartilage chondrocytes. At three different sites along the diaphysis of the femur, only a subset of osteocytes expressed sclerostin-IR and the percentage of osteocytes that expressed sclerostin-IR increased from approximately 36% to 48% in 4- vs. 24-month-old mice. In marked contrast, in the same femurs, there were ~40% fewer hypertrophic chondrocytes of articular cartilage that expressed sclerostin-IR when comparing 24- vs. 4-month-old mice. Understanding the mechanism(s) that drive these divergent changes in sclerostin-IR may provide insight into understanding and treating the age-related decline of the skeleton.     

Of Mice,Birds, and Men: The Mouse Ultrasonic Song System Has Some Features Similar to Humans and Song-Learning Birds

Humans and song-learning birds communicate acoustically using learned vocalizations. The characteristic features of this social communication behavior include vocal control by forebrain motor areas, a direct cortical projection to brainstem vocal motor neurons, and dependence on auditory feedback to develop and maintain learned vocalizations. These features have so far not been found in closely related primate and avian species that do not learn vocalizations. Male mice produce courtship ultrasonic vocalizations with acoustic features similar to songs of song-learning birds. However, it is assumed that mice lack a forebrain system for vocal modification and that their ultrasonic vocalizations are innate. Here we investigated the mouse song system and discovered that it includes a motor cortex region active during singing, that projects directly to brainstem vocal motor neurons and is necessary for keeping song more stereotyped and on pitch. We also discovered that male mice depend on auditory feedback to maintain some ultrasonic song features, and that sub-strains with differences in their songs can match each other''s pitch when cross-housed under competitive social conditions. We conclude that male mice have some limited vocal modification abilities with at least some neuroanatomical features thought to be unique to humans and song-learning birds. To explain our findings, we propose a continuum hypothesis of vocal learning.     

The Relation of Body Mass Index,Cardiorespiratory Fitness,and All‐Cause Mortality in Women

Objective: To examine the relation of body mass index (BMI), cardiorespiratory fitness (CRF), and all‐cause mortality in women. Research Methods and Procedures: A cohort of women (42.9 ± 10.4 years) was assessed for CRF, height, and weight. Participants were divided into three BMI categories (normal, overweight, and obese) and three CRF categories (low, moderate, and high). After adjustment for age, smoking, and baseline health status, the relative risk (RR) of all‐cause mortality was determined for each group. Further multivariate analyses were performed to examine the contribution of each predictor (e.g., age, BMI, CRF, smoking status, and baseline health status) on all‐cause mortality while controlling for all other predictors. Results: During follow‐up (113,145 woman‐years), 195 deaths from all causes occurred. Compared with normal weight (RR = 1.0), overweight (RR = 0.92) and obesity (RR = 1.58) did not significantly increase all‐cause mortality risk. Compared with low CRF (RR = 1.0), moderate (RR = 0.48) and high (RR = 0.57) CRF were associated significantly with lower mortality risk (p = 0.002). In multivariate analyses, moderate (RR = 0.49) and high (RR = 0.57) CRF were strongly associated with decreased mortality relative to low CRF (p = 0.003). Compared with normal weight (RR = 1.0), overweight (RR = 0.84) and obesity (RR = 1.21) were not significantly associated with all‐cause mortality. Discussion: Low CRF in women was an important predictor of all‐cause mortality. BMI, as a predictor of all‐cause mortality risk in women, may be misleading unless CRF is also considered.     

Elastoviscous Transitions of Articular Cartilage Reveal a Mechanism of Synergy between Lubricin and Hyaluronic Acid

When lubricated by synovial fluid, articular cartilage provides some of the lowest friction coefficients found in nature. While it is known that macromolecular constituents of synovial fluid provide it with its lubricating ability, it is not fully understood how two of the main molecules, lubricin and hyaluronic acid, lubricate and interact with one another. Here, we develop a novel framework for cartilage lubrication based on the elastoviscous transition to show that lubricin and hyaluronic acid lubricate by distinct mechanisms. Such analysis revealed nonspecific interactions between these molecules in which lubricin acts to concentrate hyaluronic acid near the tissue surface and promotes a transition to a low friction regime consistent with the theory of viscous boundary lubrication. Understanding the mechanics of synovial fluid not only provides insight into the progression of diseases such as arthritis, but also may be applicable to the development of new biomimetic lubricants.