The Notch pathway regulates the bone gain induced by PTH anabolic signaling

• Published in: The FASEB journal Vol. 36; no. 3; pp. e22196 - n/a
• Main Authors: Delgado‐Calle, Jesus, McAndrews, Kevin, Wu, Gerald, Orr, Ashley L., Ferrari, Adam, Tu, Xiaolin, Srinivasan, Venkatesan, Roodman, G. David, Ebetino, Frank H., Boeckman, Robert K., Bellido, Teresita
• Format: Journal Article
• Language: English
• Published: United States 01-03-2022
• Subjects: Animals; bone; Bone Resorption - genetics; Bone Resorption - metabolism; Female; Mice; Mice, Inbred C57BL; Notch; osteoblasts; osteoclasts; osteocytes; Osteocytes - metabolism; Osteogenesis; Parathyroid Hormone - metabolism; PTH; Receptor, Parathyroid Hormone, Type 1 - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; resorption; Signal Transduction; PTH; Notch; osteoclasts; resorption; bone; osteoblasts; osteocytes
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202101807R

Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone‐targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.