ABSTRACT
Fibroblasts play a central role in the lung fibrotic process. Our recent study identified a novel subpopulation of lung fibroblasts expressing meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), antifibrotic properties of which were confirmed by murine lung fibrosis model. Meflin-expressing fibroblasts were resistant to fibrogenesis induced by TGF-ß (transforming growth factor-ß), but its underlying mechanisms remain unknown. In this study, evaluation of a silica-nanoparticle-induced lung fibrosis model confirmed the antifibrotic effect of meflin via the regulation of TGF-ß signaling. We conducted comparative gene expression profiling in lung fibroblasts, which identified growth differentiation factor 10 (Gdf10) encoding bone morphogenic protein 3b (BMP3b) as the most downregulated gene in meflin-deficient cells under the profibrotic condition with TGF-ß. We hypothesized that BMP3b can be an effector molecule playing an antifibrotic role downstream of meflin. As suggested by single-cell transcriptomic data, restricted expressions of Gdf10 (Bmp3b) in stromal cells including fibroblasts were confirmed. We examined possible antifibrotic properties of BMP3b in lung fibroblasts and demonstrated that Bmp3b-null fibroblasts were more susceptible to TGF-ß-induced fibrogenic changes. Furthermore, Bmp3b-null mice exhibited exaggerated lung fibrosis induced by silica-nanoparticles in vivo. We also demonstrated that treatment with recombinant BMP3B was effective against TGF-ß-induced fibrogenesis in fibroblasts, especially in the suppression of excessive extracellular matrix production. These lines of evidence suggested that BMP3b is a novel humoral effector molecule regulated by meflin which exerts antifibrotic properties in lung fibroblasts. Supplementation of BMP3B could be a novel therapeutic strategy for fibrotic lung diseases.
Subject(s)
Growth Differentiation Factor 10 , Pulmonary Fibrosis , Animals , Fibroblasts/metabolism , Growth Differentiation Factor 10/metabolism , Lung/metabolism , Mice , Mice, Knockout , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/genetics , Silicon Dioxide/pharmacology , Transforming Growth Factor beta/metabolism , Transforming Growth Factors/metabolism , Transforming Growth Factors/pharmacologyABSTRACT
This study aimed to investigate risk factors for sarcopenia in community-dwelling older adults visiting regional medical institutions. We retrospectively analyzed medical records of 552 participants (mean age: 74.6 ± 6.7 years, males 31.3%) who underwent body composition evaluation between March 2017 and December 2018 at one of 24 medical institutions belonging to the Kadoma City Medical Association in Japan. We collected the participant's characteristics and laboratory data. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019. Sarcopenia, including severe sarcopenia, was detected in 22.3% of all participants, 17.3% of men, and 24.5% of women; rates increased with age. Multivariate logistic regression analysis revealed age (odds ratio [OR]: 2.12; 95% confidence interval [CI] 1.20-3.75), obesity (OR: 0.15; 95% CI 0.07-0.32), hypertension (OR: 0.44; 95% CI 0.25-0.76), certification of long term care (OR: 3.32; 95% CI 1.41-7.81), number of daily conversations (OR: 0.44; 95% CI 0.25-0.77), and malnutrition (OR: 2.42; 95% CI 1.04-5.60) as independent predictors of sarcopenia. Receiver operating characteristic curve analysis demonstrated that the cut-off for daily conversations defining sarcopenia was 4.8 persons. The prevalence of sarcopenia in this study was 22.3%. Besides traditional risk factors for sarcopenia, the number of daily conversations was an independent factor.
