PTHrP Modulates Chondrocyte Differentiation through AP-1 and CREB Signaling
Open Access
- 1 April 2001
- journal article
- Published by Elsevier BV in Journal of Biological Chemistry
- Vol. 276 (15), 11639-11647
- https://doi.org/10.1074/jbc.m006564200
Abstract
During the process of differentiation, chondrocytes integrate a complex array of signals from local or systemic factors like parathyroid hormone-related peptide (PTHrP), Indian hedgehog, bone morphogenetic proteins and transforming growth factor β. While PTHrP is known to be a critical regulator of chondrocyte proliferation and differentiation, the signaling pathways through which this factor acts remain to be elucidated. Here we show that both cAMP response element-binding protein (CREB) and AP-1 activation are critical to PTHrP signaling in chondrocytes. PTHrP treatment leads to rapid CREB phosphorylation and activation, while CREB DNA binding activity is constitutive. In contrast, PTHrP induces AP-1 DNA binding activity through induction of c-Fos protein expression. PTHrP activates CRE and TRE reporter constructs primarily through PKA-mediated signaling events. Both signaling pathways were found to be important mediators of PTHrP effects on chondrocyte phenotype. Alone, PTHrP suppresses maturation and stimulates proliferation of the chondrocyte cultures. However, in the presence of dominant negative inhibitors of CREB and c-Fos, these PTHrP effects were suppressed, and chondrocyte maturation was accelerated. Moreover, in combination, the effects of dominant negative c-Fos and CREB are synergistic, suggesting interaction between these signaling pathways during chondrocyte differentiation.Keywords
This publication has 61 references indexed in Scilit:
- Phosphoproteome dynamics reveal novel ERK1/2 MAP kinase substrates with broad spectrum of functionsMolecular Systems Biology, 2013
- PTHrP Expression in Chondrocytes, Regulation by TGF-β, and Interactions between Epiphyseal and Growth Plate ChondrocytesExperimental Cell Research, 2000
- BMP-6 Is an Autocrine Stimulator of Chondrocyte DifferentiationJournal of Bone and Mineral Research, 1999
- Increased Osteoblastic c-fos Expression by Parathyroid Hormone Requires Protein Kinase A Phosphorylation of the Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein at Serine 133Endocrinology, 1999
- Attenuated c-fos mRNA Induction after Middle Cerebral Artery Occlusion in CREB Knockout Mice Does Not Modulate Focal Ischemic InjuryJournal of Cerebral Blood Flow & Metabolism, 1998
- Proto-Oncogene c-fos Is Transcriptionally Regulated by Parathyroid Hormone (PTH) and PTH-Related Protein in a Cyclic Adenosine Monophosphate-Dependent Manner in Osteoblastic CellsEndocrinology, 1997
- End labeling studies of fragmented DNA in the Avian growth plate: Evidence of apoptosis in terminally differentiated chondrocytesJournal of Bone and Mineral Research, 1995
- Chondrocyte apoptosis in endochondral ossification of chick sternaDevelopmental Dynamics, 1995
- Phosphorylation of CREB by CaM-Kinase IV Activated by CaM-Kinase IV KinaseBiochemical and Biophysical Research Communications, 1995
- Activation of phosphoinositide metabolism by parathyroid hormone in growth plate chondrocytesCell Calcium, 1994