<i>Astragalus membranaceus</i> Polysaccharides Attenuate Osteoarthritis in Human Primary Chondrocytes and in Animal Model: Mechanism Study Using <scp>RNA</scp> ‐Seq and Network Pharmacology

Polysaccharides from Astragalus membranaceus polysaccharides (APS) were reported with various biological activities; however, the exact mechanisms behind anti-osteoarthritis (OA) effects of the APS are still poorly understood. Here, effects and mechanisms of the biological macromolecules against OA progression were comprehensively studied. The OA symptoms on human primary chondrocytes (HPCs) were induced by IL-1β, followed by intervention using APS. RNA-seq technique was applied to identify genes responsive to APS, and the key members were selected using the protocols of network pharmacology (NP). The results showed that APS recovered the functions of HPCs in OA conditions by modulating a network centered by seven hub genes (SOX9, JAG1, BMP4, PPARG, CXCL1, NOTCH3, and HMOX1). Mechanistically, APS activates the bioprocess for chondrocyte anabolism (SOX9), promotes cell cycle progression and migration (BMP4/Smad3/p21/CDK2), suppresses apoptosis (NF-κB/Bax/Bcl2/Caspase3), decreases ROS accumulation (Nrf2/HMOX1/NQO1), and inhibits mitophagy (NOTCH3/PINK1/Parkin/LC3-II) that rescues energy supply in OA HPCs. More importantly, intra-articular injection of APS ameliorated OA progression in the OA rat model induced by monosodium iodoacetate (MIA). Taken together, this study confirmed the therapeutic effects of APS against OA progression and elucidated its acting mechanisms in a holistic perspective, highlighting the potential of using APS-based therapeutic modalities for OA management.