The review discusses the role of Runx2 and polycystins in bone mechanotransduction, a critical process that regulates bone remodeling and regeneration. Runx2 is a key transcription factor that responds to mechanical stimuli, promoting osteoblast differentiation and bone formation. Polycystins, particularly polycystin-1 (PC1) and polycystin-2 (PC2), are mechanosensitive proteins that interact with Runx2 to modulate bone-specific signaling pathways. PC1 and PC2 form heterotetramers and interact with transcriptional coactivators like TAZ, enhancing Runx2 activity. This interaction is crucial for maintaining bone mass and anabolic responses to mechanical loading. The review highlights recent advances in understanding the molecular mechanisms of bone mechanotransduction, including the involvement of Wnt/β-catenin, YAP/TAZ, and BMP pathways. It also explores therapeutic opportunities, such as targeted magnetic stimulation, nanoparticle-based platforms, and epigenetic regulation via miRNAs and lncRNAs, to exploit the potential of Runx2 and polycystins in treating bone diseases like osteoporosis. The authors emphasize the need for further research to elucidate the complex regulatory networks and develop selective treatment approaches.The review discusses the role of Runx2 and polycystins in bone mechanotransduction, a critical process that regulates bone remodeling and regeneration. Runx2 is a key transcription factor that responds to mechanical stimuli, promoting osteoblast differentiation and bone formation. Polycystins, particularly polycystin-1 (PC1) and polycystin-2 (PC2), are mechanosensitive proteins that interact with Runx2 to modulate bone-specific signaling pathways. PC1 and PC2 form heterotetramers and interact with transcriptional coactivators like TAZ, enhancing Runx2 activity. This interaction is crucial for maintaining bone mass and anabolic responses to mechanical loading. The review highlights recent advances in understanding the molecular mechanisms of bone mechanotransduction, including the involvement of Wnt/β-catenin, YAP/TAZ, and BMP pathways. It also explores therapeutic opportunities, such as targeted magnetic stimulation, nanoparticle-based platforms, and epigenetic regulation via miRNAs and lncRNAs, to exploit the potential of Runx2 and polycystins in treating bone diseases like osteoporosis. The authors emphasize the need for further research to elucidate the complex regulatory networks and develop selective treatment approaches.