A recent publication in Genes & Diseases has delivered a compelling synthesis of the latest insights into the cellular mechanisms and therapeutic interventions for achondroplasia, the most common form of genetic dwarfism. This disorder stems primarily from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, which exerts widespread effects on skeletal development, leading to disrupted endochondral ossification, reduced chondrocyte proliferation, and abnormal bone formation.

At the core of achondroplasia's pathology lies the hyperactivation of FGFR3, which impairs not only the growth of long bones but also affects cranial, spinal, and vertebral development. The article details how FGFR3 signaling suppresses critical pathways such as Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP), and how its activation elevates cell cycle inhibitors, diminishes telomerase activity, and disrupts the cartilaginous extracellular matrix. These effects collectively lead to stunted growth, skeletal deformities, and joint complications.

The review further explores the evolving understanding of FGFR3’s role in osteogenesis, where its influence extends beyond chondrocytes to impact osteoblast differentiation and bone mineralization. FGFR3-positive cells have been identified as pivotal contributors to the formation of articular cartilage, intervertebral discs, and synovial joint structures, suggesting broader implications for skeletal stem cell biology and tissue homeostasis.

On the therapeutic front, the article highlights an expanding landscape of treatment strategies, including biological drugs, small molecule inhibitors, and gene-editing technologies. Emerging therapies aim to inhibit the FGFR3 pathway at various levels. These include monoclonal antibodies, decoy receptors like recifercept, FGFR-specific tyrosine kinase inhibitors such as infigratinib, and RNA aptamers like RBM-007. Additionally, compounds like meclozine and vosoritide target downstream signaling to enhance chondrocyte proliferation and longitudinal bone growth.

Surgical options, including limb lengthening procedures, remain viable but are accompanied by significant risks. Meanwhile, recombinant human growth hormone (rhGH) therapy has shown moderate success, particularly when combined with other treatments. Future prospects also include CRISPR-Cas9-mediated correction of FGFR3 mutations and stem cell-based regenerative approaches.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Hangang Chen, Ruobin Zhang, Min Jin, Jing Yang, Lin Chen, Yangli Xie, Advances in the mechanism and therapies of achondroplasia, Genes & Diseases, Volume 12, Issue 4, 2025, 101436, https://doi.org/10.1016/j.gendis.2024.101436

Funding Information:
National Key Research and Development Program of China 2018YFA0800802
National Natural Science Foundation of China 82122044
National Natural Science Foundation of China 81830075
Joint Funds of the National Natural Science Foundation of China U23A20411
Chongqing Science Fund for Distinguished Young Scholars CSTB2023NSCQ-JQX0023