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

Teresita Bellido, A. Afshan Ali, Lilian Plotkin, Qiang Fu, Igor Gubrij, Paula K. Roberson, Robert S. Weinstein, Charles A. O'Brien, Stavros C. Manolagas, Robert L. Jilka

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)50259-50272
Number of pages14
JournalJournal of Biological Chemistry
Volume278
Issue number50
DOIs
StatePublished - Dec 12 2003
Externally publishedYes

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Osteoblasts
Parathyroid Hormone
Bone
Bone and Bones
Degradation
Proteolysis
Ubiquitin-Protein Ligases
Osteoclasts
Apoptosis
Osteogenesis
Hormones
bcl-2 Genes
Cyclic AMP Response Element-Binding Protein
Apoptosis Regulatory Proteins
Phosphorylation
Transcription
Bone Resorption
Nutrition
Cyclic AMP-Dependent Protein Kinases
Cultured Cells

ASJC Scopus subject areas

  • Biochemistry

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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. / Bellido, Teresita; Ali, A. Afshan; Plotkin, Lilian; Fu, Qiang; Gubrij, Igor; Roberson, Paula K.; Weinstein, Robert S.; O'Brien, Charles A.; Manolagas, Stavros C.; Jilka, Robert L.

In: Journal of Biological Chemistry, Vol. 278, No. 50, 12.12.2003, p. 50259-50272.

Research output: Contribution to journalArticle

Bellido, Teresita ; Ali, A. Afshan ; Plotkin, Lilian ; Fu, Qiang ; Gubrij, Igor ; Roberson, Paula K. ; Weinstein, Robert S. ; O'Brien, Charles A. ; Manolagas, Stavros C. ; Jilka, Robert L. / 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. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 50. pp. 50259-50272.
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AU - Bellido, Teresita

AU - Ali, A. Afshan

AU - Plotkin, Lilian

AU - Fu, Qiang

AU - Gubrij, Igor

AU - Roberson, Paula K.

AU - Weinstein, Robert S.

AU - O'Brien, Charles A.

AU - Manolagas, Stavros C.

AU - Jilka, Robert L.

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