Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells.
During bone formation, multipotential mesenchymal cells proliferate and differentiate into osteoblasts, and subsequently many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors. Furthermore, the effects of PTH and PTHrP on apoptosis were dramatically dependent on cell status. In preconfluent C3H10T1/2 and MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced reduction in cell viability, which was dependent on cAMP activation. Conversely, PTH and PTHrP resulted in reduced cell viability in postconfluent cells, which was also dependent on cAMP activation. Further, the proapoptotic-like effects were associated with an inhibition of Akt phosphorylation. These data suggest that parathyroid hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at least in part via the protein kinase A pathway.
Chen
Hen-Li
HL
Department of Periodontics, Prevention, and Geriatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Demiralp
Burak
B
Schneider
Abraham
A
Koh
Amy J
AJ
Silve
Caroline
C
Wang
Cun-Yu
CY
McCauley
Laurie K
LK
D016475:3T3 Cells; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D015675:Osteocalcin / Q000096:biosynthesis / Q000378:metabolism; D010281:Parathyroid Hormone / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D014162:Transfection
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018016:Receptors, Parathyroid Hormone; D015675:Osteocalcin; D003907:Dexamethasone; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases