Obesity is a well-established risk factor for cardiovascular disease (CVD), but the underweight population of body mass index (BMI) below 18.5 kg/m² has not been an object of concern. The objective of this study is to investigate whether underweight could be an independent risk factor for CVD in a population-based cross-sectional study. Cross-sectional data of 2013 Behavioral Risk Factor Surveillance System (BRFSS) database encompassing 491,773 US adult subjects were used to assess risk for CVD. Primary outcomes were the incidence and relative risks (RRs) of CVD including stroke, heart attack/myocardial infarction, or coronary artery disease according to BMI category. All analyses used weighted sampling probabilities of data source. The underweight population had a 19.7% greater risk of CVD than did the normal-weight, and the overweight and obese population had a 50% and 96% increased risk, respectively. When adjusted with covariates, the relative risk for CVD elevated in underweight population (adjusted RR 1.34 [95% confidence interval (CI) 1.335–1.348]). Conversely, the adjusted relative risk was significantly attenuated in the obese group (adjusted RR 1.149 [95% CI 1.147–1.151]) and it was even insignificant in the overweight group (adjusted RR 1.00 [95% CI 1.000–1.003]). In subanalysis for each CVD category, being underweight among BMI status was the strongest independent risk factor for stroke (adjusted RR 1.441 [95% CI 1.431–1.450]), heart attack/ myocardial infarction (MI) (adjusted RR 1.23 [95% CI 1.217–1.233]), and angina/coronary artery disease (adjusted RR 1.20 [95% CI 1.189–1.206]). Especially among the population below 40-year old, relative risk estimates remained increased in the underweight population; persons who were underweight had a 2.3-fold greater adjusted relative risk of CVD as compared with those with normal weight when we stratified with age. Underweight below BMI 18.5 kg/m² may be another risk factor for CVD, and CVD risk of the overweight and obese population largely depended on other comorbidities accompanied by obesity.

Jang AR, et al. Immune Netw. 2019 Jan;19:e2. /Synapse/10.4110/in.2019.19.e2

Objective: Interleukin‐10 (IL‐10) is a pleiotropic immunoregulatory cytokine with a chondroprotective effect that is elevated in cartilage and synovium in patients with osteoarthritis. However, the role of IL‐10 during endochondral bone formation and its mechanism of action have not been elucidated.Methods: IL‐10^–/– mice and IL‐10–treated tibial organ cultures were used to study loss and gain of IL‐10 functions, respectively, during endochondral bone formation. Primary chondrocytes from the long bones of mouse embryos were cultured with and without IL‐10. To assess the role of IL‐10 in chondrogenic differentiation, we conducted mesenchymal cell micromass cultures.Results: The lengths of whole skeletons from IL‐10^–/– mice were similar to those of their wild‐type littermates, although their skull diameters were smaller. The tibial growth plates of IL‐10^–/– mice showed shortening of the proliferating zone. Treatment with IL‐10 significantly increased tibial lengths in organ culture. IL‐10 also induced chondrocyte proliferation and hypertrophic differentiation in primary chondrocytes in vitro. Mechanistically, IL‐10 activated STAT‐3 and the Smad1/5/8 and ERK‐1/2 MAP kinase pathways and induced the expression of bone morphogenetic protein 2 (BMP‐2) and BMP‐6 in primary chondrocytes. Furthermore, the blocking of BMP signaling attenuated the IL‐10–mediated induction of cyclin D1 and RUNX‐2 in primary chondrocytes and suppressed Alcian blue and alkaline phosphatase staining in mesenchymal cell micromass cultures.Conclusion: These results indicate that IL‐10 acts as a stimulator of chondrocyte proliferation and chondrogenic or hypertrophic differentiation via activation of the BMP signaling pathway.

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in articular cartilage and the loss of CS-GAG occurs early in OA. As a major component of perichondral matrix interacting directly with chondrocytes, the active turnover of CS can affect to break the homeostasis of chondrocytes. Here we employ CS-based 3-dimensional (3D) hydrogel scaffold system to investigate how the degradation products of CS affect the catabolic phenotype of chondrocytes. The breakdown of CS-based ECM by the chondroitinase ABC (ChABC) resulted in a hypertrophy-like morphologic change in chondrocytes, which was accompanied by catabolic phenotypes, including increased MMP-13 and ADAMTS5 expression, nitric oxide (NO) production and oxidative stress. The inhibition of Toll-like receptor 2 (TLR2) or TLR4 with OxPAPC (TLR2 and TLR4 dual inhibitor) and LPS-RS (TLR4-MD2 inhibitor) ameliorated these catabolic phenotypes of chondrocytes by CS-ECM degradation, suggesting a role of CS breakdown products as damage-associated molecular patterns (DAMPs). As downstream signals of TLRs, MAP kinases, NF-kB, NO and STAT3-related signals were responsible for the catabolic phenotypes of chondrocytes associated with ECM degradation. NO in turn reinforced the activation of MAP kinases as well as NFkB signaling pathway. Thus, these results propose that the breakdown product of CS-GAG can recapitulate the catabolic phenotypes of OA.

An activation of osteoclasts and subchondral bone remodeling is a major histologic feature of early-stage osteoarthritis (OA), which can be accompanied by an increase of calcium (Ca) and phosphate (Pi) level in the subchondral milieu. Considering articular cartilage gets most of nutrition from subchondral bone by diffusion, these micro-environmental changes in subchondral bone can affect the physiology of articular chondrocytes. Here, we have shown that Ca is increased and co-localized with Pi in articular cartilage of early-stage OA. The Ca-Pi complex increased the production of MMP-3 and MMP-13 in the hypertrophic chondrocytes, which was dependent on nuclear factor-kappa B (NF-kB), p38 and extracellular signal-regulated kinase (Erk) 1/2 mitogen-activated protein (MAP) kinase and Signal transducer and activator of transcription 3 (STAT3) signaling. The Ca-Pi complexes increased the expression of endocytosis markers, and the inhibition of the formation of the Ca-Pi complex ameliorated the Ca-Pi complex-mediated increases of MMPs expression in hypertrophic chondrocytes. Our data provide insight regarding the Ca-Pi complex as a potential catabolic mediator in the subchondral milieu and support the pathogenic role of subchondral bone in the early stages of cartilage degeneration.