ASPN encodes asporin, a small leucine-rich proteoglycan that functions as a negative regulator of TGF-β and BMP signaling pathways across multiple tissues. In periodontal ligament, asporin inhibits BMP2-induced mineralization by blocking BMPR1B receptor binding and SMAD activation, preserving the non-ossified state of tooth-supporting tissues. In articular cartilage, asporin negatively regulates chondrogenesis by inhibiting TGF-β/Smad signaling, playing a critical role in cartilage homeostasis 1. ASPN is a susceptibility locus for osteoarthritis 2, with proposed mechanisms involving TGF-β pathway modulation and collagen mineralization 1. Beyond skeletal tissues, asporin serves as a protective factor in pulmonary arterial hypertension, where it is upregulated as a compensatory response and inhibits proliferation and TGF-β/pSMAD2/3 signaling in pulmonary artery smooth muscle cells 3. Asporin also associates with developmental dysplasia of the hip pathogenesis through its role in chondrogenesis 4. In fibrotic diseases including systemic sclerosis and heart failure, ASPN+ fibroblasts contribute to excessive extracellular matrix accumulation 56. These findings indicate asporin functions as a multitissue regulator of TGF-β signaling with implications for skeletal and fibrotic pathologies.