Search Results (149)

Myostatin (GDF8) is a member of the transforming growth factor-β (TGF-β) superfamily. Myostatin gene mutations or inhibition of the Myostatin/Activin pathway results in increased skeletal muscle mass, demonstrating its role as a negative regulator of skeletal muscle. Myostatin blockade is a promising strategy for increasing muscle mass in myopathies such as Duchenne Muscular Dystrophy (DMD); however, it faces considerable challenges in clinical translation, in part due to the progressive nature of the disease. Here we tested the ability of JA16 monoclonal antibody-mediated myostatin blockade to improve the dystrophic phenotype in newborn mdx mice (an animal model of DMD). Myostatin inhibition led to significant increases in muscle size, fiber number and cross-sectional area along with increased absolute force alongside reduced post-eccentric contraction force drop and reduced serum creatine kinase. We used the Multiparametric Muscle Improvement Score (MMIS) to objectively quantitate benefits in this preclinical study and determined that the magnitude of improvements exceeded those reported using the exact same intervention in older mdx mice treated for the same duration. This study demonstrates an age-dependent aspect of this intervention and suggests that earlier interventions may provide greater therapeutic benefits. Full article

The 15-leucine-rich repeat containing membrane protein (LRRC15) is a transmembrane protein derived from the leucine-rich repeat (LRR) superfamily that participates in various cell–cell and cell–extracellular matrix interactions, regulating fibrogenesis, vascular invasion, tumorigenesis, and the formation of the innate immune barrier to drive specific antiviral responses. LRRC15, whose expression is reportedly induced by TGF-β and IL-1β stimulation, was recently found to be associated with the development of skeletal diseases, and its presence has been related to the pathophysiological processes of osteoporosis, osteoarthritis and rheumatoid arthritis. Various transmembrane and intracellular signaling transductions are involved in LRRC15-mediated molecular functions, including integrin, NF-κB, Wnt/β-catenin, etc. Additionally, LRRC15 is considered a novel mesenchymal protein and an important biomarker for the occurrence and development of osteosarcoma. Understanding the role of LRRC15 in the bone, joint and tumor microenvironment will facilitate the development of new therapeutic options—particularly LRRC15-based target therapies—for skeletal diseases. Full article

Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-β) superfamily, thereby regulating diverse physiological processes, including regulation of skeletal muscle, adipose, and bone homeostasis. FST also promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles and metabolic health in mice. Given the emerging association between brown adipose tissue (BAT) activation and reduced atherosclerosis, we investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area and positively correlated with the expression of multiple adipose browning-associated genes. Adeno-associated viral delivery of Fst (AAV1-FST344) in Ldlr^−/− mice significantly reduced aortic lesion area, improved plasma lipid profiles, and decreased expression of adhesion (VCAM1) and inflammatory (iNOS, TNF-α) markers in white adipose tissue (WAT), liver, and heart. Fst gene delivery also markedly increased uncoupling protein 1 (UCP1) expression in WAT, consistent with WAT browning. Integrated correlation analyses of Fst expression with tissue metabolites, together with plasma metabolite–lesion associations identified in the HMDP, implicated the arginase 1 (Arg1)-mediated metabolic pathway as a key regulator of atherogenesis. Consistent with these findings, Arg1 expression was significantly elevated in WAT, liver, and heart of AAV1-FST344-treated mice and in wild-type versus Fst-knockout mouse embryonic fibroblasts (MEFs). Immunostaining localized Arg1 predominantly to CD68⁺ macrophages in heart and liver. Given recent evidence identifying Arg1 as a novel mediator of efferocytosis, these findings suggest that Arg1 may promote macrophage metabolic reprogramming and resolution of inflammation by enhancing the clearance of apoptotic cells. Furthermore, Fst gene delivery increased the expression of fibroblast growth factor 21 (Fgf21) and adiponectin (AdipoQ) in WAT. Collectively, these findings identify Fst as a novel anti-atherogenic regulator that protects against vascular disease by promoting adipose browning, improving lipid metabolism, and activating Arg1-mediated metabolic pathways. Full article

The transforming growth factor-beta (TGF-β) superfamily regulates diverse biological processes, including proliferation, differentiation, apoptosis, tissue remodeling, and reproductive signaling across metazoans. Here, we performed a genome-wide characterization of the TGF-β gene family in donkey (Equus asinus, ASM1607732v2) using comparative genomics and bioinformatics analyses, with horse (Equus caballus, EquCab3.0) as a reference to investigate evolutionary conservation and functional divergence. Genome assemblies and proteomes were retrieved from NCBI, and TGF-β genes were identified using BLASTp and HMMER searches (Pfam PF00019), followed by phylogenetic, conserved motif, synteny, Ka/Ks, mutation prediction, subcellular localization, and tissue-specific expression analyses. We identified 40 TGF-β genes in donkeys, exceeding the numbers reported in several mammals, suggesting possible lineage-specific expansion or differential gene retention within Equidae. Phylogenetic and motif analyses demonstrated strong evolutionary conservation across the two principal clades (TGF-β-like and BMP-like). Four segmental duplications were identified, with Ka/Ks ratios ranging from 0.28 to 0.43, indicating strong purifying selection on duplicated genes. Synteny analysis revealed extensive collinearity with the horse genome, supporting conserved equid genomic architecture. Comparative sequence analysis identified 160 amino acid variants, including 11 predicted deleterious mutations in key genes (GDF6, GDF9, GDF10, BMP15, and RGMA), suggesting potential functional divergence associated with reproductive and developmental pathways. Importantly, transcriptomic validation using publicly available donkey RNA-seq tissue expression data (NCBI BioProject: PRJNA1017964) revealed distinct tissue-specific expression patterns, with reproductive tissues (ovary and uterus) displaying enriched expression of TGF-β/BMP signaling components, particularly TGFBR1, TGFBR2, TGFB1, BMP2, BMP4, and BMP7, while canonical fecundity genes (GDF9 and BMP15) exhibited ovary-associated expression. This receptor-dominant signaling profile may have a coordinated TGF-β regulatory network underlying folliculogenesis, reproductive tissue remodeling, and fertility-related processes in donkeys. Subcellular localization predictions showed that most proteins (22/40) were extracellularly localized, consistent with conserved signaling functions. Together, this study provides the first integrated genomic and tissue-expression atlas of the donkey TGF-β superfamily, offering new insights into equid-specific evolutionary conservation, reproductive signaling, and functional divergence. Full article

Segmental bone defects and age-related osteoarthritis (OA) are clinically challenging in terms of treatment. Although preclinical studies have demonstrated efficacy for bone defect healing and OA using ex vivo gene therapy or biomaterial sustained-release delivery, few such treatments have translated into clinical therapies due to safety concerns. Bone morphogenetic proteins belong to the transforming growth factor β (TGFβ) superfamily and are effective in bone and cartilage regeneration/repair. Among BMPs, BMP4 is not only effective in promoting bone and cartilage repair but also promotes stem cell renewal potential and exhibits anti-aging effects. Therefore, the aim of this study is to investigate whether human BMP4 mRNA encapsulated in lipid nanoparticles (hBMP4 mRNA/LNP) can promote bone and cartilage repair. In vitro data demonstrated that hBMP4 mRNA/LNP-treated human MSCs secreted BMP4 protein, as detected by ELISA, and enhanced osteogenic differentiation. In vivo results demonstrated that hBMP4 mRNA/LNP at a 50 µg dose promoted limited new bone formation only at 2 weeks after creation of defect in critical-sized calvarial bone defects in aged mice when delivered using fibrin sealant hydrogel, as revealed by micro-CT and histology. However, intra-articular injection (IA) of lower doses (2.5 and 5 µg) in aged mice knee joints prevented cartilage loss, as demonstrated by micro-CT; decreased OARSI histology scores; and improved cartilage-specific matrix COL2. hBMP4 mRNA/LNP at a 5 μg dose significantly increased SOX9⁺ cells per normalized cartilage area as well as the percentage of SOX9⁺ cells in the cartilage area. hBMP4 mRNA/LNP treatment showed a trend of pain alleviation and did not change serum hyaluronic acid levels. In conclusion, human BMP4 mRNA encapsulated in lipid nanoparticles improved cartilage repair and delayed cartilage degeneration in aged mice, while having a limited effect on bone healing, even at a higher dosage. These results suggest that hBMP4 mRNA encapsulated with lipid nanoparticles represents a promising treatment for age-related OA. Full article

Myostatin (Mstn), a well-characterized member of the transforming growth factor-β (TGF-β) superfamily, serves as a key negative regulator of skeletal muscle mass. Its overactivation is closely associated with the pathogenesis of various musculoskeletal and metabolic disorders. Over the past decades, inhibiting Mstn has emerged as a promising therapeutic strategy to promote muscle growth. A range of Mstn-targeted inhibitors has been developed, yielding encouraging preclinical and clinical outcomes. These include small molecules, monoclonal antibodies, peptibodies, and gene therapy-based approaches. This review summarizes the biological structure and function of Mstn, provides a comprehensive overview of recent advances in Mstn-targeted therapeutics, and offers critical insights into future directions for drug development and clinical translation. Full article

Heart failure (HF) prognosis, particularly readmission and mortality, remains poor irrespective of advances in its management. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-beta (TGF-β) superfamily that arises as a promising biomarker to improve HF management, still despite two decades of extensive investigation some issues remain controversial. We performed a search in PubMed using the following Medical Subject Headings (MeSH) to identify relevant studies published in the last five years (after the latest updates of the guidelines by major Scientific Societies): “Growth differentiation factor-15 (GDF-15)”, “heart failure”, “prognosis” and “diagnosis”. The search was supplemented by data previous to this period, considered of utmost importance. A total of 115 articles written in English were retrieved. Extensive evidence supports GDF-15 as an independent predictor of adverse outcomes across the heterogeneous HF spectrum and its addition to risk scores based on traditional biomarkers improves prognostic power. However, limited tissue specificity restricts its diagnostic value. Tailored treatment strategies and its role as a therapeutic target remain speculative, as the effect of HF therapies on GDF-15 levels is unclear and clinical trials have been unsuccessful. Large prospective studies are needed to validate its reliability for routine clinical use. Full article

Chromatin is a dynamic cellular structure basically constituted by nucleosomes, which consist of a DNA sequence wrapped around an octameric histones core. Histone synthesis and transport, nucleosome formation and proper chromatin assembly is an ordered and stepwise process guided by histone chaperones. Several families of histone chaperones have been identified and one of them is the nucleosome assembly protein (NAP) superfamily. Members of this family have been involved not only in chromatin constitution and regulation but also in several other cellular processes, such as nucleocytoplasmic shuttling, DNA replication, transcription and cell-cycle regulation. Testis specific protein Y-like 2 (TSPYL2) is a peculiar member of the NAP superfamily of histone chaperone. This protein has been initially isolated as a nuclear antigen in patients affected by discoid lupus erythematosus and as a TGF-β target. Its ability to bind histones has been demonstrated. In addition, TSPYL2 has been reported to regulate transcription, cell-cycle progression and the DNA-damage response, independently of its role in chromatin organization. In accordance with its multiple functions, defects in TSPYL2 have been associated with different diseases, mainly cancer and neurodevelopmental abnormalities. In this review we summarize and discuss the multiple cellular functions of TSPYL2, pointing out new and unexpected aspects like a sex-related activity and their relationship with different diseases. Full article

Anti-Müllerian hormone (AMH), a member of the transforming growth factor-β (TGF-β) superfamily, has been widely recognized for its role in reproductive endocrinology and is regarded as one of the “gold standards” for evaluating ovarian age and fertility potential. In recent years, the focus of research on AMH has gradually expanded from the reproductive system to the skeletal system. Although the specific mechanism of its action in bone-metabolism-related diseases and associated signaling pathways still requires in-depth exploration, existing studies have confirmed—through cell experiments, animal models, and clinical data—the important role of AMH in maintaining bone health. Here, the significance of AMH in research on female osteoporosis is reviewed, the current signaling pathway mechanisms by which AMH regulates bone metabolism are summarized, and the relevant clinical research results are discussed. This work features three unique contributions: first, the logical progression of AMH research from reproductive regulation to bone metabolism is explicitly clarified; second, multi-level evidence is integrated to form a complete regulatory network, avoiding fragmented discussions of individual findings; and third, concrete clinical translation pathways and targeted solutions for existing limitations are proposed, rather than merely outlining general directions. This review aims to identify new biomarkers for the early screening of osteoporosis and therapeutic targets, ultimately promoting the formulation of personalized prevention and treatment strategies. Additionally, as a key factor linking ovarian function and bone health, the AMH research concepts and methods summarized herein can be extended to other hormone-related bone metabolism disorders. Full article

Background/Objectives: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) represents one of the major contributors to morbidity and mortality in Rheumatoid arthritis (RA), yet its underlying molecular mechanisms remain incompletely defined. Activin A, a member of the transforming growth factor-β (TGF-β) superfamily, has emerged as a key regulator of inflammation, fibroblast activation, and tissue remodeling. However, its role in RA patients with interstitial lung disease (ILD) has not been fully elucidated. We aimed to investigate circulating levels of Activin A, Follistatin-Like Protein-1 (FSTL1), and Follistatin-Like Protein-3 (FSTL3) in patients with RA, RA-ILD, idiopathic pulmonary fibrosis (IPF), and healthy controls and explore their associations with disease activity and pulmonary function parameters. Methods: This cross-sectional study included 90 participants: healthy controls (n = 20), RA (n = 25), RA-ILD (n = 21), and IPF (n = 24). Serum biomarkers were quantified using validated enzyme-linked immunosorbent assays (ELISAs). Clinical characteristics, inflammatory markers, disease activity indices, and pulmonary function tests were recorded. Group comparisons and correlation analyses were performed using appropriate parametric and non-parametric statistical methods. Results: Circulating Activin A levels were progressively increased from controls to RA, RA-ILD, and IPF, with significantly higher concentrations in all disease groups relative to controls. FSTL1 levels were significantly reduced in RA-ILD patients compared with RA and controls, while FSTL3 levels were markedly elevated in IPF. Activin A did not correlate with disease activity indices or pulmonary function parameters, whereas FSTL1 correlated positively with diffusing capacity of the lungs for carbon monoxide and disease duration, and FSTL3 showed an inverse association with lactate dehydrogenase. Conclusions: Activin A may be associated with the fibroinflammatory burden in both RA-ILD and IPF. The observation of altered circulating levels of Follistatin-like proteins—key regulatory molecules with multifaceted biological functions—suggests that the underlying pathogenesis is complex and governed by tightly regulated, interconnected signaling pathways. Full article

Obesity is increasingly recognized not only as a metabolic disorder but also as a condition marked by the structural and functional deterioration of skeletal muscle and tendon tissues. Central to this process is the dysregulation of the extracellular matrix (ECM) resulting in fibrosis and ectopic fat accumulation, factors that contribute to impaired tissue mechanics. Myostatin (GDF-8), a member of the TGF-β superfamily, is known as a negative regulator of muscle mass. It can also mediate interaction between adipose and other tissues including muscles and tendons. In obesity, elevated myostatin levels have been reported to be associated with insulin resistance, muscle atrophy, and activation of SMAD2/3 signaling, while experimental and preclinical studies indicate that myostatin inhibition can improve glucose homeostasis and increase lean mass. Emerging evidence suggests that myostatin also plays a critical role in muscle ECM and tendon remodeling. Restoring its physiological levels may help reverse ECM disorganization and reduce tissue fragility associated with musculotendinous dysfunction. This review highlights the multifaceted role of myostatin in obesity, beyond its role in muscle catabolism, to include modulation of structural integrity, metabolism, and mechanical adaptability of the musculotendinous system. Understanding how myostatin responds to metabolic stress and affects biomechanical remodeling offers novel insights into obesity-related muscle and tendon dysfunction. Full article

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials—PULSAR, STELLAR, ZENITH, and HYPERION—demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept’s therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management. Full article

The Transforming Growth Factor-β (TGF-β) superfamily comprises highly conserved cytokines that orchestrate key cellular functions, including proliferation, differentiation, and apoptosis. Within the ovary, TGF-β family members serve as pivotal regulators of folliculogenesis, exerting stage-specific actions from embryonic germ cell development to advanced follicular maturation. During fetal development, activins and SMAD-dependent signaling pathways are essential for primordial germ cell proliferation, survival, and the breakdown of germ cell cysts, enabling the establishment of the primordial follicle pool. Throughout folliculogenesis, TGF-β supports follicle activation, promotes the transition from dormant to growing follicles, stimulates granulosa cell proliferation, sustains follicular viability, and modulates steroidogenesis through theca cell regulation. Notably, anti-müllerian hormone, a TGF-β family member, plays a central role in inhibiting premature follicle recruitment and serves as a key biomarker of ovarian reserve. Dysregulation of TGF-β signaling contributes to various ovarian disorders, including polycystic ovary syndrome and premature ovarian insufficiency. A deeper understanding of these complex signaling networks is critical for identifying novel therapeutic targets and advancing clinical interventions in female reproductive pathologies. This review provides an integrated overview of the roles of the TGF-β superfamily in ovarian physiology and its contributions to disease development. Full article

Transforming growth factor β (TGF-β) superfamily members are critical in teleost sex determination and differentiation. Tgfb2b is an important TGF-β ligand gene exhibiting dominant expression in the ovary of Chinese tongue sole (Cynoglossus semilaevis), yet its function in sex regulation remains unclear. In the present study, the gene expression pattern, transcriptional regulation, and knockdown effect were examined. Its expression persisted and showed a gradual increase throughout ovarian development from 3 months to 1.5 years post-hatching. In situ hybridization (ISH) revealed that the gene was distributed across oocytes at stages I–III, while scarcely detectable in the testis. The transcriptional factors CCAAT/enhancer binding protein α (C/EBPα) and Jun proto-oncogene AP-1 transcription factor subunit (c-Jun) could repress the activity of tgfb2b promoter. In vitro knockdown of tgfb2b in C. semilaevis ovarian cells led to downregulation of its downstream genes (e.g., smad1 and smad2) as well as other sex-related genes (e.g., foxl2 and esr2b). Moreover, multi-omics analysis indicated that, in C. semilaevis gonads, a miRNA named novel-m0083-3p showed an opposite expression pattern with tgfb2b and might have a binding site with the gene. By dual-luciferase assay, tgfb2b was validated to be directly targeted and suppressed by the miRNA. These results demonstrate that tgfb2b plays a significant role in ovarian differentiation and development. Further functional and molecular studies on the interplay between tgfb2b and the foxl2–cyp19a–esr axis will help elucidate the regulatory network underlying sex development in teleost. Full article

Growth Differentiation Factor-15 (GDF-15) is a stress-responsive cytokine belonging to the Transforming Growth Factor-beta (TGF-β) superfamily. Initially identified as macrophage inhibitory cytokine-1 (MIC-1), GDF-15 is expressed in various tissues and markedly upregulated under pathological conditions involving inflammation, oxidative stress, and tissue injury. Notably, GDF-15 upregulation has been associated with several cardiovascular events, such as heart failure, atrial fibrillation, atherosclerosis, coronary artery disease, and stroke. Furthermore, it has been observed that GDF-15, either alone or in combination with other cardiac biomarkers, can provide valuable complementary information enhancing risk assessment, early detection of cardiovascular events, and prediction of adverse outcomes. GDF-15 can be measured in various body fluids, using different methods. Immunoassays are widely employed and offer good sensitivity and reproducibility; however, variability between methods and potential interference from genetic variants highlight the need for standardization. This review summarizes current insights into GDF-15, with emphasis on its quantification methods, biological functions in cardiovascular diseases, and its emerging role as a diagnostic and prognostic biomarker. Full article