The injection of bone mesenchymal stem cells (BMSCs) for osteoarthritis (OA) treatment fails to address the disrupted extracellular microenvironment, limiting the differentiation and paracrine functions of BMSCs and resulting in suboptimal therapeutic outcomes. Proteoglycans (PGs) promote cell differentiation, tissue repair, and microenvironment remodeling. This study investigated the potential of combining PGs with BMSCs to increase the efficacy of OA treatment.