GDF5 is a growth factor primarily involved in skeletal development and bone/cartilage formation. Mechanistically, GDF5 positively regulates chondrogenic differentiation through high-affinity binding to BMPR1B, activating SMAD1/5/8 phosphorylation and downstream signaling 1. It also negatively regulates chondrogenesis through interaction with noggin (NOG), providing dual control of cartilage development. Beyond skeletal biology, GDF5 prevents excessive muscle loss during aging and denervation through SMAD4-dependent pathways 2. Recent evidence demonstrates that GDF5-lineage fibroblasts, originating from the embryonic joint interzone, are critical in synovial joint homeostasis and become pathogenic in inflammatory arthritis through IL-6-Yap-Snail axis activation 34. Clinically, GDF5 variants associate with multiple skeletal dysplasias including acromesomelic dysplasia, brachydactyly, and symphalangism 5. GDF5 is a major osteoarthritis susceptibility locus identified through genome-wide association studies 67. Additionally, GDF5 polymorphisms link to age-related muscle weakness in older adults 8. Therapeutic potential exists: recombinant GDF5 administration reverses sarcopenia-associated muscle wasting, improves neuromuscular junction integrity, and induces 'rejuvenating' transcriptomic changes in aged muscle 2, suggesting clinical applications for age-related neuromuscular decline.