PTHrP Modulates Chondrocyte Differentiation through AP-1 and CREB Signaling

Ionescu, Andreia; Schwarz, Edward M.; Vinson, Charles; Puzas, J. Edward; Rosier, Randy N.; Reynolds, Paul; O’Keefe, Regis J.

doi:10.1074/jbc.m006564200

Cited by 111 publications

(94 citation statements)

References 58 publications

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“…PKA phosphorylates and activates CREB, and PTH activates AP1 family members such as Fos/Jun. Although these PKAassociated molecules are involved in bone development, recent evidence suggests a role for AP1 and CREB in differentiation rather than in proliferation (59). Our data indicate that the inhibition of PKA does not block cAMP-induced mitogenic action in cells of bone origin, regardless of whether the cells express or lack 95-kDa B-Raf.…”

Section: Dual Functionality Of Pth On Cell Proliferation 22196mentioning

confidence: 49%

New Signaling Pathway for Parathyroid Hormone and Cyclic AMP Action on Extracellular-regulated Kinase and Cell Proliferation in Bone Cells

Fujita

Meguro

Fukuyama

et al. 2002

Journal of Biological Chemistry

114

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cAMP signaling, activated by extracellular stimuli such as parathyroid hormone, has cell type-specific effects important for cellular proliferation and differentiation in bone cells. Recent evidence of a second enzyme target for cAMP suggests divergent effects on extracellular-regulated kinase (ERK) activity depending on Epac/Rap1/B-Raf signaling. We investigated the molecular mechanism of the dual functionality of cAMP on cell proliferation in clonal bone cell types. MC3T3-E1 and ATDC5, but not MG63, express a 95-kDa isoform of BRaf. cAMP stimulated Ras-independent and Rap1-dependent ERK phosphorylation and cell proliferation in B-Raf-expressing cells, but inhibited growth in B-Raflacking cells. The mitogenic action of cAMP was blocked by the ERK pathway inhibitor PD98059. In B-Raf-transduced MG63 cells, cAMP stimulated ERK activation and cell proliferation. Thus, B-Raf is the dominant molecular switch that permits differential cAMP-dependent regulation of ERK with important implications for cell proliferation in bone cells. These findings might explain the dual functionality of parathyroid hormone on osteoblastic cell proliferation.In mammals, parathyroid hormone (PTH) 1 is the most important hormone affecting bone growth and resorption. It shares the PTH/PTH-related protein (PTHrP) receptor (PPR) with PTHrP (1-8), the only other known endogenous ligand for PPR. A series of gene disruption studies of PTHrP and/or PPR in mice (9 -12) has indicated that PTH action on PPR can generate either bone-forming or bone-resorbing signaling, reflecting the complexity and heterogeneity of the osteoblast population and/or the regulatory microenvironment.PPR belongs to the class II G-protein-coupled receptor subfamily of receptors (7). PTH-(1-84), the natural hormone, and its congeners (e.g. PTH-(1-34)) strongly couple with PPR to activate adenylate cyclase and generate a cAMP signal (8). Several lines of evidence indicate that this signal activates ERKs (extracellular-regulated kinase) in the pathway that promotes bone growth in vivo and in vitro (13-17). However, how cAMP activates ERK is still unknown. The most important target of cAMP is protein kinase A (PKA), but activation of PKA is known to counteract the Ras/Raf-1/MEK signaling pathway (18 -20) that is essential for activation of ERK and stimulation of cell proliferation (21-23). Thus, we have been in search of the pathway linking the cAMP signal to ERK activation.Recently, a second enzyme target of cAMP, cAMP-guanine nucleotide exchange factor (cAMP-GEF)/Epac, emerged as a Rap1-specific GEF (26, 27), indicating that cAMP can modulate ERKs via the Epac/Rap1/B-Raf pathway in a PKA-and Rasindependent manner (24 -27). We now show that a variety of bone cell lines, clonal and primary, constitutively express the components of this pathway in a cell type-specific manner. Modulation of cell proliferation through cAMP signaling is regulated primarily by the expression pattern of B-Raf splice variants, and B-Raf appears to function as a molecular switch in this signaling s...

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Section: Dual Functionality Of Pth On Cell Proliferation 22196mentioning

confidence: 49%

New Signaling Pathway for Parathyroid Hormone and Cyclic AMP Action on Extracellular-regulated Kinase and Cell Proliferation in Bone Cells

Fujita

Meguro

Fukuyama

et al. 2002

Journal of Biological Chemistry

114

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“…We and others have shown that PTH/PTHrP signaling stimulates cyclin D1 transcription in chondrocytes (55)(56)(57). Recent work has identified a Rho-specific activator, the guanine nucleotide exchange factor CDEP, as a target of PTH in chondrocytes (58, 59).…”

Section: Resultsmentioning

confidence: 99%

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

Wang

Woods

Sabari

et al. 2004

Journal of Biological Chemistry

118

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Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation. RhoA overexpression in chondrogenic ATDC5 cells results in increased proliferation and a marked delay of hypertrophic differentiation, as shown by decreased induction of alkaline phosphatase activity, mineralization, and expression of the hypertrophic markers collagen X, bone sialoprotein, and matrix metalloproteinase 13. These effects are accompanied by activation of cyclin D1 transcription and repression of the collagen X promoter by RhoA. In contrast, inhibition of Rho/ROCK signaling by the pharmacological inhibitor Y27632 inhibits chondrocyte proliferation and accelerates hypertrophic differentiation. Dominant-negative RhoA also inhibits induction of the cyclin D1 promoter by parathyroid hormone-related peptide. Finally, Y27632 treatment partially rescues the effects of RhoA overexpression. In summary, we identify the RhoA/ROCK signaling pathway as a novel and important regulator of chondrocyte proliferation and differentiation.The development and growth of endochondral bones (such as ribs, vertebrae, and the long bones of vertebrate limbs) are regulated through the highly controlled rates of proliferation and hypertrophic differentiation of growth plate chondrocytes (1-3). In the growth plate, chondrocytes first undergo a series of cell divisions along the longitudinal axis of the growing bone, thereby forming characteristic columns of clonal cells. Chondrocytes then withdraw from the cell cycle and begin to increase their cell volume until reaching the fully differentiated state of hypertrophic chondrocytes. Transition from a proliferating to a hypertrophic phenotype involves numerous changes in gene expression, for example the induction of the collagen X (4, 5), matrix metalloproteinase 13 (6, 7), and bone sialoprotein (BSP) 1 (8 -10) genes. The latter two genes are also expressed by osteoblasts, suggesting similar biological properties of hypertrophic chondrocytes and osteoblasts. The fate of hypertrophic chondrocytes is still debated, but it appears that the majority of these cells undergo apoptosis and are replaced by bone tissue (11). Longitudinal growth of endochondral bones therefore requires both proliferation and differentiation-associated hypertrophy of growth plate chondrocytes.Disruption of chondrocyte proliferation and/or differentiation by gene mutations commonly results in chondrodysplasias that are characterized by skeletal deformities and reduced growth (12)(13)(14). Mutations in genes encoding extracellular matrix molecules, growth factors, receptors, and transcription factors have been identified as causes of several chondrodysplasias. Fo...

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“…Ectopic expression of Fos in developing chicken limb buds by retroviral microinjection causes truncation of the cartilage in the long bones of the injected leg; this is due to chondrodysplasia caused by severely retarded differentiation of the proliferating chondrocytes into mature chondrocytes, hypertrophy of chondrocytes, and delays in precartilagenous condensation (11). AP-1 also plays an essential role in the regulation of chondrocyte differentiation by parathyroid hormone-related protein through induction of c-Fos protein expression (12). Genetic studies in mice have provided compelling evidence for the role of AP-1 family members in skeletal development in vivo.…”

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confidence: 99%