Stimulation of Extracellular Signal-regulated Kinases and Proliferation in Rat Osteoblastic Cells by Parathyroid Hormone Is Protein Kinase C-dependent

Swarthout, John T.; Doggett, Teresa A.; Lemker, Joseph L.; Partridge, Nicola C.

doi:10.1074/jbc.m007400200

Cited by 131 publications

(113 citation statements)

References 65 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…In addition, treatment of embryonic chick periosteal cells with PTH for 5-30 minutes stimulated proliferation [71]. Although pro-mitotic actions of PTH have also been reported in cultures of osteoblastic cells maintained for 24 hours or longer in the presence of PTH [72,73], these responses do not appear to be relevant to the anabolism caused by repeated transient PTH exposure. In view of the available in vivo evidence against a substantial contribution of increased osteoblast progenitor proliferation in response to intermittent PTH [62], it seems reasonable to conclude that the proliferative effects of short term PTH exposure seen in vitro reflects either a phenomenon that is highly favored in the tissue culture environment, or the response of a progenitor that makes a comparatively small contribution to the increase in osteoblast number in remodeling cancellous bone.…”

Section: Effects Of Intermittent Pth On the Replication And Differentmentioning

confidence: 96%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

608

520

View full text Add to dashboard Cite

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of antiapoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPARγ may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

show abstract

Section: Effects Of Intermittent Pth On the Replication And Differentmentioning

confidence: 96%

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Jilka

2007

Bone

608

520

View full text Add to dashboard Cite

show abstract

“…Most previous data suggested that regulation of osteoblast differentiation by GPCR was mainly mediated via cAMP/PKA signaling (15), and little attention has been given to how G␣ qmediated signaling affects bone formation (16,17). In vitro, continued treatment of calvariae or osteoblastic cells with PTH has been shown to inhibit type I collagen expression and to increase osteocalcin expression largely via cAMP-dependent pathways (18,19).…”

Section: Discussionmentioning

confidence: 99%

Continuous Activation of Gαq in Osteoblasts Results in Osteopenia through Impaired Osteoblast Differentiation

Ogata

Kawaguchi

Chung

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

We explored the role of G␣ q -mediated signaling on skeletal homeostasis by selectively expressing a constitutively active G␣ q (mutation of Q209L) in osteoblasts. Continuous signaling via G␣ q in mouse osteoblastic MC3T3-E1 cells impaired differentiation. Mice that expressed the constitutively active G␣ q transgene in cells of the osteoblast lineage exhibited severe osteopenia in cortical and trabecular bones. Osteoblast number, bone volume, and trabecular thickness were reduced in transgenic mice, but the osteoclasts were unaffected. Osteoblasts from transgenic mice showed impaired differentiation and matrix formation. In the presence of a protein kinase C inhibitor GF109203X, this impairment was not seen, indicating mediation by the protein kinase C pathway. We propose that continuous activation of the G␣ q signal in osteoblasts plays a crucial, previously unrecognized role in bone formation.

show abstract

“…A number of signaling transduction pathways have been associated with PTH (8,9,(47)(48)(49)(50). For example, Boguslawski et al (16) showed that PKA and PKC pathways cooperatively interact in PTH-mediated OCN gene expression in rat and human osteoblast cell lines.…”

Section: Fig 5 Effect Of Pth Treatment On the Binding Of Nuclear Exmentioning

confidence: 99%

“…PTH functions through the PTH-1 receptor, a G protein-coupled receptor that is expressed in osteoblasts (5-7). Binding of PTH to its receptor activates multiple intracellular signaling pathways that involve cyclic cAMP, inositol phosphates, intracellular Ca 2ϩ , protein kinases A and C (2), and the extracellular signal-regulated kinase/ mitogen-activated protein kinase (MAPK) pathway (8,9).…”

mentioning

confidence: 99%

Parathyroid Hormone Induction of the Osteocalcin Gene

Jiang

Franceschi

Boules

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Parathyroid hormone (PTH) is an important peptide hormone regulator of bone formation and osteoblast activity. However, its mechanism of action in bone cells is largely unknown. This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells. PTH increased the levels of osteocalcin mRNA 4 -5-fold in both cell types. PTH also stimulated transcriptional activity of a 1.3-kb fragment of the mouse osteocalcin gene 2 (mOG2) promoter. Inhibitor studies revealed a requirement for protein kinase A, protein kinase C, and mitogen-activated protein kinase pathways in the PTH response. Deletion of the mOG2 promoter sequence from ؊1316 to ؊116 caused no loss in PTH responsiveness whereas deletion from ؊116 to ؊34 completely prevented PTH stimulation. Interestingly, this promoter region does not contain the RUNX2 binding site shown to be necessary for PTH responsiveness in other systems. Nuclear extracts from PTH-treated MC3T3-E1 cells exhibited increased binding to OSE1, a previously described osteoblast-specific enhancer in the mOG2 promoter. Furthermore, mutation of OSE1 in DNA transfection assays established the requirement for this element in the PTH response. Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins.Parathyroid hormone (PTH) 1 is a major regulator of calcium homeostasis. PTH has catabolic and anabolic effects on osteoblasts and bone in vitro and in vivo, which depend on the temporal pattern of administration; continuous administration decreases bone mass whereas intermittent administration increases bone mass (1-4). PTH functions through the PTH-1 receptor, a G protein-coupled receptor that is expressed in osteoblasts (5-7). Binding of PTH to its receptor activates multiple intracellular signaling pathways that involve cyclic cAMP, inositol phosphates, intracellular Ca 2ϩ , protein kinases A and C (2), and the extracellular signal-regulated kinase/ mitogen-activated protein kinase (MAPK) pathway (8, 9).Osteocalcin (OCN), a 5700-dalton ␥-carboxyglutamic acidcontaining noncollagenous protein, is a major component of the bone extracellular matrix. Although the functions of OCN are poorly understood, gene deletion studies suggest possible functions in bone remodeling (10). The expression of OCN is regulated by a number of calcitropic hormones and growth factors including 1,25-dihydroxy vitamin D 3 (11-13), glucocorticoids (14, 15), PTH (16), bone morphogenetic proteins (17), basic fibroblast growth factor 2 (18), tumor necrosis factor-␣ (19), and transforming growth factor ␤ (20). A number of transcription factors that bind to specific regions of the osteocalcin gene promoter have also been identified. These factors include AP-1 family members (21, 22), MSX-2/HOX 8.1 (23, 24), DLX-5 (25), CCAAT/enhancer binding proteins (26), and RUNX2 (27), the osteoblast-specific product of the Cbfa1 gene. These f...

show abstract

Stimulation of Extracellular Signal-regulated Kinases and Proliferation in Rat Osteoblastic Cells by Parathyroid Hormone Is Protein Kinase C-dependent

Cited by 131 publications

References 65 publications

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Continuous Activation of Gαq in Osteoblasts Results in Osteopenia through Impaired Osteoblast Differentiation

Parathyroid Hormone Induction of the Osteocalcin Gene

Contact Info

Product

Resources

About