Journal
BONE
Volume 103, Issue -, Pages 159-167Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2017.06.027
Keywords
PTH; Notch; Rbpjk; Osteoblast; Osteocyte
Categories
Funding
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [AR063049, AR068160]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK045227]
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Parathyroid hormone (PTH) and Notch receptors regulate bone formation by governing the function of osteoblastic cells. To determine whether PTH interacts with Notch signaling as a way to control osteoblast function, we tested the effects of PTH on Notch activity in osteoblast- and osteocyte-enriched cultures. Notch signaling was activated in osteoblast-enriched cells from wild-type C57BL/6J mice following exposure to the Notch ligand Delta-like (D11)1 or by the transient transfection of the Notch intracellular domain (NICD), the transcriptionally active fragment of Notch1. To induce Notch signaling in osteocyte-enriched cultures, a murine model of Notch2 gain-of-function was used. PTH opposed the stimulatory effects of Dll1 on Hey1, Hey2 and HeyL mRNA levels in osteoblast-enriched cells and suppressed the expression of selected Notch target genes in osteocyte-enriched cultures, either under basal conditions or in the context of Notch2 gain-of-function. Induction of Notch signaling in osteocytes did not alter the inhibitory effect of PTH on Sost expression, but reduced the stimulation of Tnfsf1 1 mRNA levels by PTH. In agreement with these in vitro observations, male mice administered with PTH displayed suppressed Hey1 and HeyL expression in parietal bones. Transactivation experiments with a Notch reporter construct and electrophoretic mobility shift assays in osteoblast-enriched cells suggest that PTH acts by decreasing the capacity of Rbpjk to bind to DNA. In conclusion, downregulation of Notch in osteoblasts and osteocytes may represent a mechanism contributing to the anabolic effects of PTH in bone. (C) 2017 Elsevier Inc. All rights reserved.
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