This review explores the roles of Runx2 and polycystins in bone mechanotransduction and their potential therapeutic applications. Runx2 is a critical transcription factor involved in osteoblast differentiation and bone formation, regulated by various post-translational modifications and signaling pathways. Polycystins, particularly PC1 and PC2, are mechanosensitive proteins that interact with Runx2 to regulate bone mass and mechanotransduction. The study highlights the complex interplay between these proteins in bone remodeling and regeneration, emphasizing their roles in bone homeostasis and disease. Mechanotransduction involves the conversion of mechanical signals into biochemical responses, which is essential for bone development and maintenance. The review discusses the molecular mechanisms underlying bone mechanotransduction, including the involvement of Wnt/β-catenin, YAP/TAZ, and other signaling pathways. It also examines the therapeutic potential of targeting Runx2 and polycystins, including the use of miRNAs, magnetic stimulation, and nanoparticle-based platforms. The study underscores the importance of understanding these mechanisms for developing novel treatments for bone diseases such as osteoporosis. The review concludes that further research is needed to elucidate the complex signaling networks involving Runx2 and polycystins, which could lead to more effective therapeutic strategies for bone-related disorders.This review explores the roles of Runx2 and polycystins in bone mechanotransduction and their potential therapeutic applications. Runx2 is a critical transcription factor involved in osteoblast differentiation and bone formation, regulated by various post-translational modifications and signaling pathways. Polycystins, particularly PC1 and PC2, are mechanosensitive proteins that interact with Runx2 to regulate bone mass and mechanotransduction. The study highlights the complex interplay between these proteins in bone remodeling and regeneration, emphasizing their roles in bone homeostasis and disease. Mechanotransduction involves the conversion of mechanical signals into biochemical responses, which is essential for bone development and maintenance. The review discusses the molecular mechanisms underlying bone mechanotransduction, including the involvement of Wnt/β-catenin, YAP/TAZ, and other signaling pathways. It also examines the therapeutic potential of targeting Runx2 and polycystins, including the use of miRNAs, magnetic stimulation, and nanoparticle-based platforms. The study underscores the importance of understanding these mechanisms for developing novel treatments for bone diseases such as osteoporosis. The review concludes that further research is needed to elucidate the complex signaling networks involving Runx2 and polycystins, which could lead to more effective therapeutic strategies for bone-related disorders.