Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells.
We previously demonstrated that activation of the Parathyroid Hormone Receptor (PTH1R) in osteoblastic cells increases the Notch ligand Jagged1 and expands hematopoietic stem cells (HSC) through Notch signaling. However, regulation of Jagged1 by PTH in osteoblasts is poorly understood. The present study demonstrates that PTH treatment increases Jagged1 levels in a subpopulation of osteoblastic cells in vivo and in UMR106 osteoblastic cells in vitro. Since PTH(1-34) activates both Adenylate Cyclase/Protein Kinase A (AC/PKA) and Protein Kinase C (PKC) downstream of the PTH1R in osteoblastic cells, we independently determined the effect of either pathway on Jagged1. Activation of AC with Forskolin or PKA with PTH(1-31) or cell-permeable cAMP analogues increased osteoblastic Jagged1. This PTH-dependent Jagged1 increase was blocked by H89 and PKI, specific PKA inhibitors. In contrast, PKC activation with phorbol ester (PMA) or PTH(13-34) did not stimulate Jagged1 expression, and PTH-dependent Jagged1 stimulation was not blocked by Gö6976, a conventional PKC inhibitor. Therefore, PTH treatment stimulates osteoblastic Jagged1 mainly through the AC/PKA signaling pathway downstream of the PTH1R. Since Jagged1/Notch signaling has been implicated not only in stromal-HSC interactions but also in osteoblastic differentiation, Jagged1 may play a critical role in mediating the PTH-dependent expansion of HSC, as well as the anabolic effect of PTH in bone.
Weber
Jonathan M
JM
Endocrine Division, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue Box 693 Rochester, NY 14642, USA.
Forsythe
Shaula R
SR
Christianson
Christina A
CA
Frisch
Benjamin J
BJ
Gigliotti
Benjamin J
BJ
Jordan
Craig T
CT
Milner
Laurie A
LA
Guzman
Monica L
ML
Calvi
Laura M
LM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases