Endothelial-to-osteoblast conversion maintains bone homeostasis through Kindlin-2/Piezo1/TGFβ/Runx2 axis

The article elaborates on the molecular mechanisms underlying endothelial-to-osteoblast conversion. The authors explore how endothelial cells, through the activation of Kindlin-2, Piezo1, and the TGFβ signaling pathway, promote osteoblast differentiation. They discuss how these factors influence the expression of Runx2, a key transcription factor for osteogenesis, and how this cascade contributes to bone tissue homeostasis. Through a combination of in vitro and in vivo experiments, the study provides evidence supporting the role of this pathway in bone repair and homeostasis. The work underscores the importance of endothelial cells in bone biology, challenging the traditional view of their solely vascular function.

Key findings from the study include:

1. Promotion of EC-to-OSB by Kindlin-2 Knockdown: The study found that knocking down Kindlin-2 in HUVECs and in an endothelial-specific knockout mouse model significantly promoted EC-to-OSB, as evidenced by morphological changes and increased expression of osteogenic markers.
2. Increase in Bone Mass Mediated by Runx2: μCT analysis and genetic manipulation in mice showed that the increase in bone mass caused by endothelial Kindlin-2 haploinsufficiency was mediated through Runx2, suggesting a crucial role of Runx2 in the activation of EC-to-OSB pathways.
3. Regulation of Piezo1 Protein Stability by Kindlin-2: Kindlin-2 was found to interact with Trim28, enhancing Piezo1 ubiquitination and degradation. The study demonstrated that Kindlin-2 deficiency increased Piezo1 protein levels, which were reversed by inhibiting ubiquitination or promoting degradation.
4. Piezo1 Activation and Its Role in EC-to-OSB: Activation of Piezo1 using a specific agonist promoted EC-to-OSB and increased osteogenic marker expression. This further supported the role of Piezo1 in bone formation and its regulation by Kindlin-2.

The findings of this study provide significant insights into the mechanisms of bone homeostasis. The endothelial-to-osteoblast conversion, regulated by Kindlin-2, Piezo1, TGFβ, and Runx2, represents a novel pathway in bone formation and regeneration. These findings may have implications for developing new therapeutic strategies for bone diseases such as osteoporosis, by targeting the molecular signals involved in endothelial-to-osteoblast transdifferentiation. The study opens up possibilities for enhancing bone repair through mechanotransduction-based therapies. The work entitled “ Endothelial-to-Osteoblast Conversion maintains bone homeostasis through Kindlin-2/Piezo1/TGFβ/Runx2 axis ” was published on Protein & Cell (published on Dec. 2, 2024).