The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Matthew B. Greenblatt, Jae Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger Davis, Laurie H. Glimcher

Research output: Contribution to journalArticle

Abstract

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

Original languageEnglish (US)
Pages (from-to)2457-2473
Number of pages17
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

Fingerprint

p38 Mitogen-Activated Protein Kinases
Osteoblasts
Homeostasis
Bone and Bones
Mitogen-Activated Protein Kinase Kinases
Transcription Factors
Phosphotransferases
Cleidocranial Dysplasia
CREB-Binding Protein
Osteogenesis
Osteoporosis
Ligands
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Greenblatt, M. B., Shim, J. H., Zou, W., Sitara, D., Schweitzer, M., Hu, D., ... Glimcher, L. H. (2010). The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. Journal of Clinical Investigation, 120(7), 2457-2473. https://doi.org/10.1172/JCI42285

The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. / Greenblatt, Matthew B.; Shim, Jae Hyuck; Zou, Weiguo; Sitara, Despina; Schweitzer, Michelle; Hu, Dorothy; Lotinun, Sutada; Sano, Yasuyo; Baron, Roland; Park, Jin Mo; Arthur, Simon; Xie, Min; Schneider, Michael D.; Zhai, Bo; Gygi, Steven; Davis, Roger; Glimcher, Laurie H.

In: Journal of Clinical Investigation, Vol. 120, No. 7, 01.07.2010, p. 2457-2473.

Research output: Contribution to journalArticle

Greenblatt, MB, Shim, JH, Zou, W, Sitara, D, Schweitzer, M, Hu, D, Lotinun, S, Sano, Y, Baron, R, Park, JM, Arthur, S, Xie, M, Schneider, MD, Zhai, B, Gygi, S, Davis, R & Glimcher, LH 2010, 'The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice', Journal of Clinical Investigation, vol. 120, no. 7, pp. 2457-2473. https://doi.org/10.1172/JCI42285
Greenblatt, Matthew B. ; Shim, Jae Hyuck ; Zou, Weiguo ; Sitara, Despina ; Schweitzer, Michelle ; Hu, Dorothy ; Lotinun, Sutada ; Sano, Yasuyo ; Baron, Roland ; Park, Jin Mo ; Arthur, Simon ; Xie, Min ; Schneider, Michael D. ; Zhai, Bo ; Gygi, Steven ; Davis, Roger ; Glimcher, Laurie H. / The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 7. pp. 2457-2473.
@article{984a20cedfe24fcf871a9d1b7f4c16ec,
title = "The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice",
abstract = "Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.",
author = "Greenblatt, {Matthew B.} and Shim, {Jae Hyuck} and Weiguo Zou and Despina Sitara and Michelle Schweitzer and Dorothy Hu and Sutada Lotinun and Yasuyo Sano and Roland Baron and Park, {Jin Mo} and Simon Arthur and Min Xie and Schneider, {Michael D.} and Bo Zhai and Steven Gygi and Roger Davis and Glimcher, {Laurie H.}",
year = "2010",
month = "7",
day = "1",
doi = "10.1172/JCI42285",
language = "English (US)",
volume = "120",
pages = "2457--2473",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

TY - JOUR

T1 - The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

AU - Greenblatt, Matthew B.

AU - Shim, Jae Hyuck

AU - Zou, Weiguo

AU - Sitara, Despina

AU - Schweitzer, Michelle

AU - Hu, Dorothy

AU - Lotinun, Sutada

AU - Sano, Yasuyo

AU - Baron, Roland

AU - Park, Jin Mo

AU - Arthur, Simon

AU - Xie, Min

AU - Schneider, Michael D.

AU - Zhai, Bo

AU - Gygi, Steven

AU - Davis, Roger

AU - Glimcher, Laurie H.

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

AB - Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

UR - http://www.scopus.com/inward/record.url?scp=77954972964&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954972964&partnerID=8YFLogxK

U2 - 10.1172/JCI42285

DO - 10.1172/JCI42285

M3 - Article

VL - 120

SP - 2457

EP - 2473

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -