scholarly journals Suppression of p38α MAPK Signaling in Osteoblast Lineage Cells Impairs Bone Anabolic Action of Parathyroid Hormone

2016 ◽  
Vol 31 (5) ◽  
pp. 985-993 ◽  
Author(s):  
Cyril Thouverey ◽  
Joseph Caverzasio
Keyword(s):  
Parathyroid Hormone ◽  
Mapk Signaling ◽  
Anabolic Action ◽  
P38α Mapk ◽  
Osteoblast Lineage

scholarly journals Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4377-4387 ◽  
Author(s):  
Cyril Thouverey ◽  
Joseph Caverzasio
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Estrogen Deficiency ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
P38α Mapk ◽  
Mapk Inhibitors ◽  
Osteoblast Lineage

Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38α MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38α-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor κB ligand and IL-6 expression in mice lacking p38α in osteoblasts and osteocytes. Finally, TNFα or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38α signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38α MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor κB ligand and IL-6 production.

Effect of Parathyroid Hormone on MAPK Signaling and Calcification Markers in Human Intervertebral Disk Cells

2012 ◽  
Vol 2 (1_suppl) ◽  
pp. s-0032-1319991-s-0032-1319991
Author(s):  
P. Madiraju ◽  
R. Gawri ◽  
J. Antoniou ◽  
F. Mwale
Keyword(s):  
Parathyroid Hormone ◽  
Mapk Signaling ◽  
Intervertebral Disk

scholarly journals Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice

2012 ◽  
Vol 302 (10) ◽  
pp. E1183-E1188 ◽  
Author(s):  
Nabanita S. Datta ◽  
Tareq A. Samra ◽  
Abdul B. Abou-Samra
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Physiological Role ◽  
Receptor Internalization ◽  
Mineral Density ◽  
Trabecular Thickness ◽  
Receptor Complexes ◽  
Diaphyseal Bone ◽  
Anabolic Action

Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

scholarly journals Parathyroid hormone 1-34 and skeletal anabolic action

2017 ◽  
Vol 6 (1) ◽  
pp. 14-21 ◽  
Author(s):  
L. Osagie-Clouard ◽  
A. Sanghani ◽  
M. Coathup ◽  
T. Briggs ◽  
M. Bostrom ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Anabolic Action

scholarly journals Site-specific polyubiquitination differentially regulates parathyroid hormone receptor–initiated MAPK signaling and cell proliferation

2018 ◽  
Vol 293 (15) ◽  
pp. 5556-5571 ◽  
Author(s):  
Qiangmin Zhang ◽  
Kunhong Xiao ◽  
Hongda Liu ◽  
Lei Song ◽  
Jennifer C. McGarvey ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Hormone Receptor ◽  
Mapk Signaling ◽  
Site Specific ◽  
Parathyroid Hormone Receptor

scholarly journals EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone

2013 ◽  
Vol 28 (4) ◽  
pp. 912-925 ◽  
Author(s):  
Farzin M Takyar ◽  
Stephen Tonna ◽  
Patricia WM Ho ◽  
Blessing Crimeen-Irwin ◽  
Emma K Baker ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Anabolic Response ◽  
Osteoblast Lineage

scholarly journals Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

2015 ◽  
Vol 291 (4) ◽  
pp. 1631-1642 ◽  
Author(s):  
Partha Sinha ◽  
Piia Aarnisalo ◽  
Rhiannon Chubb ◽  
Ingrid J. Poulton ◽  
Jun Guo ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Phospholipase C ◽  
Osteoblast Differentiation ◽  
Bone Volume ◽  
Trabecular Bone Volume ◽  
Male And Female ◽  
Osteoblast Lineage

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-GsαOsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1–34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-GsαOsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-GsαOsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.

TGF-β-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-β1-induced MKK3-p38 MAPK activation and stimulation of type I collagen

2007 ◽  
Vol 292 (5) ◽  
pp. F1471-F1478 ◽  
Author(s):  
Sung Il Kim ◽  
Joon Hyeok Kwak ◽  
Mareena Zachariah ◽  
Yanjuan He ◽  
Lin Wang ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Type I Collagen ◽  
Mesangial Cells ◽  
Constitutive Expression ◽  
Mapk Signaling ◽  
Signaling Cascade ◽  
Type I ◽  
Protein Levels ◽  
Collagen Expression ◽  
P38α Mapk

We have previously demonstrated that transforming growth factor-β1 (TGF-β1) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257–47262, 2002). In the present study, we investigated the functional role of upstream TGF-β-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-β1 signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-β1 was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-β1 stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-β1-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38α MAPK activity by ectopic expression of either TAB1 or wild-type p38α MAPK resulted in enhanced TGF-β1-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-β1. In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

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