Aug 2026· Children· Vol 13, pp. 1121· 0 citations· 42 references
Medicine
TL;DR
Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature and vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity.
Abstract
Highlights What are the main findings? FGFR3 hyperactivation disrupts growth-plate signaling and endochondral bone growth. Vosoritide confirms that achondroplasia can be treated with disease-modifying therapy. What are the implications of the main findings? Treatment is shifting toward targeted, mechanism-based therapies. Long-term studies are needed to confirm benefits beyond growth velocity. Abstract Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence.
PURPOSE OF REVIEW
Inclusion body myositis (IBM) is the most prevalent acquired myopathy in adults over 50 years of age, yet effective disease-modifying therapy has remained elusive. The longstanding debate over whether degeneration or inflammation is the primary driver has now given way to a model of bidirectional interplay. This review critically appraises advances published between January 2025 and June 2026, encompassing molecular pathomechanisms, early diagnostic strategies, disease-modifying therapies, and rehabilitation.
RECENT FINDINGS
A pivotal mechanistic advance is the demonstration that TDP-43 nuclear depletion in IBM myonuclei generates cryptic exon-derived neoantigens that directly activate CD8+ T cells, molecularly unifying cell-autonomous degeneration and adaptive immune activation. In parallel, mitochondrial DNA leakage activates the cGAS-STING innate immune pathway prior to T cell infiltration. An endogenous compensatory mechanism involving the NORAD-Pumilio regulatory axis has also been identified. Clinically, preliminary data from the Phase 2/3 MUSCLE trial suggest a potential 50% slowing of progression in mild-to-moderate IBM with the anti-KLRG1 antibody ulviprubart, pending full peer-reviewed publication, while novel diagnostic and rehabilitation strategies further advance personalized care.
SUMMARY
A molecular cascade from cell-autonomous TDP-43 dysfunction to cryptic epitope-driven immune activation could underlie the pathogenesis of IBM. Personalized multidisciplinary care integrating early diagnosis, targeted disease-modifying therapy, and advanced rehabilitation represents the emerging treatment paradigm.
Naoki Suzuki, R. Izumi, Kensuke Ikeda· Current Opinion in Neurology· 1 citation
Background: RASopathies constitute a group of rare genetic disorders caused by mutations in genes along the canonical RAS/MAPK signaling pathway, affecting cell growth and differentiation. These syndromes, which include Noonan syndrome (NS), are characterized by developmental delays, distinctive facial dysmorphia, and cardiac defects, notably hypertrophic cardiomyopathy (HCM). Despite their prevalence and impact, therapeutic options for RASopathies remain limited. Rigosertib, a novel dual RAS/MAPK and PI3K/AKT pathway inhibitor, is currently in clinical trials for treatment of melanoma and recessive dystrophic epidermolysis bullosa. Here, we identify rigosertib as a candidate therapy for RAF1-associated HCM. Methods: We performed a drug screen of clinically relevant compounds in transgenic Drosophila models of RASopathies to identify candidate therapeutics. Cardiac-targeted Drosophila models expressing RASopathy-associated transgenes were used to evaluate the effects of rigosertib on cardiac hypertrophy and compare its efficacy with the MEK inhibitor trametinib. Therapeutic efficacy was further assessed in a mammalian model using Raf1L613V/+ knock-in mice treated with rigosertib for six weeks. Cardiac structure and function were evaluated by echocardiography, histology, and molecular analyses, including assessment of cardiomyocyte (CM) size, fetal gene expression, and ERK/AKT signaling. Additional Noonan syndrome-associated phenotypes, including skeletal growth and craniofacial abnormalities, were also evaluated. Results: Rigosertib was effective across a panel of transgenic Drosophila RASopathy models, suggesting activity against multiple disease variants. In cardiac-targeted fly models, rigosertib reduced cardiac hypertrophy and outperformed trametinib. In Raf1L613V/+ mice, six weeks of treatment significantly improved left ventricular chamber dimension, posterior wall thickness, heart mass, and CM size, resulting in reversal of cardiac hypertrophy. Rigosertib also normalized fetal gene expression and inhibited ERK and AKT signaling in primary CMs. In addition to reversing cardiac pathology, rigosertib significantly improved other Noonan syndrome-associated features, including increased bone growth and correction of craniofacial abnormalities. Conclusions: Together, our findings suggest rigosertib normalizes and reverses RASopathy-associated HCM and other NS-associated syndromic features, supporting its development as a promising treatment for RAF1-associated HCM and, potentially, other RASopathy-dependent pathologies. This study not only highlights the therapeutic potential of rigosertib but also demonstrates the utility of an integrated approach using Drosophila and mammalian models to elucidate drug effects across complex biological systems.
Levi Legler, K. Marchetti, Bing Xu et al.· Circulation· 0 citations
BACKGROUND
Metabolic dysfunction-associated steatohepatitis (MASH) is a leading indication for liver transplantation, and fibrosis stage most strongly predicts clinical outcomes. Pharmacologic treatment is now available with resmetirom and semaglutide holding conditional approval.
AIMS
To describe the therapeutic landscape for MASH with a focus on anti-fibrotic impact.
METHODS
Narrative review of Phase 2 and 3 trials, meta-analyses, epidemiological data, and trial registries.
RESULTS
Historically, drugs targeting downstream fibrogenic or inflammatory pathways have had limited success in advanced development, whereas those improving metabolic dysfunction have had fared better. Fibrosis improvement by at least one stage was seen with resmetirom in up to 26% versus 14% placebo after 52 weeks and with semaglutide in 37% versus 22% after 72 weeks. Several agents in development (e.g., fibroblast growth factor 21 analogues, as well as dual and triple incretin agonists, pan-peroxisome proliferator-activated receptor agonist) report encouraging Phase 2 results, with Phase 3 trials ongoing. Compensated cirrhosis requires a distinct approach related to its fibrosis heterogeneity and burden of portal hypertension. This requires a delicate balance between efficacy and event rates that is further complicated by current regulatory constraints.
CONCLUSIONS
Fibrosis improvement in MASH is attainable by available drugs with further promise from emerging therapies. The link between treatment induced histological improvement or improvement in noninvasive tests and reduction in clinical outcomes remains unproven. A rich therapeutic pipeline with the promise of combination regimens and increased focus non-invasive endpoints suggests that the future looks bright for patients living with fibrotic MASH.
Bisphosphonates (BPs) are cornerstone therapeutic agents for the management of metabolic bone disorders and skeletal complications associated with malignant tumors. However, their long-term administration is accompanied by the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). In recent years, the pathogenesis of BRONJ has remained a major focus at the intersection of osteoimmunology and oral medicine. This review systematically summarizes the latest advances in the understanding of BRONJ pathogenesis, including the direct disruption of osteoclast differentiation and bone remodeling coupling by bisphosphonates, the systemic reprogramming of immune cell subsets and inflammatory signaling pathways, the multifaceted suppression of angiogenesis and the endothelial–stromal–immune axis, and the toxic impairment of oral soft tissue repair capacity. Building upon these mechanistic insights, we further discuss the modifying and synergistic effects of local oral risk factors, microbial dysbiosis, systemic comorbidities, and genetic susceptibility on the initiation and progression of BRONJ. Furthermore, emerging therapeutic strategies targeting these pathogenic mechanisms are highlighted, including restoration of small GTPase prenylation through modulation of metabolic pathways, reconstruction of T-cell subset homeostasis via immunomodulatory approaches, enhancement of local vascularization through pro-angiogenic interventions, and preservation of soft tissue barrier integrity. Collectively, this review provides a comprehensive and multidimensional overview of the pathological landscape of BRONJ and offers a theoretical framework for clinical risk stratification and the development of personalized prevention and treatment strategies.
Yao Li, Shengao Qin, Jiaqi Wang et al.· Current Issues in Molecular...· 0 citations
OBJECTIVES
Chondrocalcinosis, characterized by calcium crystal deposition within articular cartilage, affects 5-15% of the general population and has recently been identified as an osteoarthritis risk factor. However, Its biological pathways remain unclear. We conducted a genome-wide association study of radiographically defined chondrocalcinosis knee and hand to identify its genetic determinants.
METHODS
GWAS analyses of knee, hand, and combined chondrocalcinosis included up to 9,317 Rotterdam Study participants, with replication inthe Versus Arthritis Osteoarthritis Genetics study and the Multicenter Osteoarthritis Study. Translational annotation prioritized effector genes. Associations between circulating thyroid-stimulating hormone (TSH) and knee chondrocalcinosis were evaluated in the Rotterdam Study (n = 2,892).
RESULTS
We identified two genome-wide significant loci for knee chondrocalcinosis: a novel signal (rs62424495) at the ENPP1-locus (β = -0.21, P = 2.6 × 10-9) and a previously reported signal (rs6927663) at the RNF144B-locus (β = 0.12, P = 8.8 × 10-10). Translational genomic analyses prioritized ENPP1 and RNF144B as candidate effector genes, with evidence indicating that the chondrocalcinosis variant likely affects RNF144B regulation in thyroid tissue.The lead variant colocalized with circulating TSH levels (β = 0.027, P = 2 × 10-14). population analysis found that higher TSH levels were cross-sectionally associated with presence and severity of knee chondrocalcinosis.
CONCLUSIONS
These findings identify genetic loci for radiographic chondrocalcinosis and offer hypothesis-generating evidence of thyroid-related pathways in its susceptibility, providing insight into molecular mechanisms underlying joint mineralization.
Ya-Hong Wu, Yanning Xu, P. Okoro et al.· Arthritis & Rheumatology· 0 citations
Evaluating critically how historical nosology, molecular pathology and emerging gene-directed interventions relate to one another is evaluated, and to determine which conclusions the accessible evidence can currently sustain are evaluated.
S. Bittmann, E. Luchter, E. Moschüring-Alieva· Journal of Advances in Medic...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
