Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism.
It is unknown why sustained elevation of parathyroid hormone (PTH) stimulates bone resorption, whereas intermittent administration stimulates bone formation. We show in mice that daily injections of PTH attenuate osteoblast apoptosis, thereby increasing osteoblast number, bone formation rate, and bone mass, but do not affect osteoclast number. In contrast, sustained elevation of PTH, achieved either by infusion or by raising endogenous hormone secretion with a calcium-deficient diet, does not affect osteoblast apoptosis but increases osteoclast number. Attenuation of apoptosis by PTH in cultured osteoblastic cells requires protein kinase A-mediated phosphorylation and inactivation of the pro-apoptotic protein Bad as well as transcription of survival genes, like Bcl-2, mediated by CREB (cAMP response element-binding protein) and Runx2. But, PTH also increases proteasomal proteolysis of Runx2. Moreover, the anti-apoptotic effect of PTH is prolonged by inhibition of proteasomal activity, by overexpressing a dominant negative form of the E3 ligase (ubiquitin-protein isopeptide ligase) that targets Runx2 for degradation (Smurf1), or by overexpressing Runx2 itself. The duration of the anti-apoptotic effect of PTH, thus, depends on the level of Runx2, which in turn is decreased by PTH via Smurf1-mediated proteasomal proteolysis. The self-limiting nature of PTH-induced survival signaling might explain why intermittent administration of the hormone is required for bone anabolism.
Bellido
Teresita
T
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Ali
A Afshan
AA
Plotkin
Lilian I
LI
Fu
Qiang
Q
Gubrij
Igor
I
Roberson
Paula K
PK
Weinstein
Robert S
RS
O'Brien
Charles A
CA
Manolagas
Stavros C
SC
Jilka
Robert L
RL
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001862:Bone Resorption; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000378:metabolism*; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053245:RANK Ligand; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D003609:Dactinomycin; D012313:RNA; D017868:Cyclic AMP-Dependent Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium