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Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival
Journal article   Open access   Peer reviewed

Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival

G J Eaton, Q-S Zhang, C Diallo, A Matsuzawa, H Ichijo, M J Steinbeck, T A Freeman and Shaoxiong Zhang
Cell death & disease, v 5(11), pp e1522-e1522
13 Nov 2014
DOI: https://doi.org/10.1038/cddis.2014.480
PMID: 25393478
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1038/cddis.2014.480View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Animals Apoptosis - drug effects Aporphines - pharmacology Bone and Bones - cytology Bone and Bones - drug effects Bone and Bones - metabolism Calcification, Physiologic - drug effects Cell Differentiation - drug effects Cell Survival - drug effects Chondrocytes - cytology Chondrocytes - drug effects Chondrocytes - metabolism Chondrogenesis - drug effects Chondrogenesis - genetics Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - metabolism Gene Expression Regulation, Developmental Hydrogen Peroxide - antagonists & inhibitors Hydrogen Peroxide - pharmacology MAP Kinase Kinase Kinase 5 - antagonists & inhibitors MAP Kinase Kinase Kinase 5 - genetics MAP Kinase Kinase Kinase 5 - metabolism Mice Mice, Knockout Osteogenesis - drug effects Osteogenesis - genetics Protein Kinase Inhibitors - pharmacology Quinolines - pharmacology Signal Transduction Staurosporine - antagonists & inhibitors Staurosporine - pharmacology
Endochondral ossification is the result of chondrocyte differentiation, hypertrophy, death and replacement by bone. The careful timing and progression of this process is important for normal skeletal bone growth and development, as well as fracture repair. Apoptosis Signal-Regulating Kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK), which is activated by reactive oxygen species and other cellular stress events. Activation of ASK1 initiates a signaling cascade known to regulate diverse cellular events including cytokine and growth factor signaling, cell cycle regulation, cellular differentiation, hypertrophy, survival and apoptosis. ASK1 is highly expressed in hypertrophic chondrocytes, but the role of ASK1 in skeletal tissues has not been investigated. Herein, we report that ASK1 knockout (KO) mice display alterations in normal growth plate morphology, which include a shorter proliferative zone and a lengthened hypertrophic zone. These changes in growth plate dynamics result in accelerated long bone mineralization and an increased formation of trabecular bone, which can be attributed to an increased resistance of terminally differentiated chondrocytes to undergo cell death. Interestingly, under normal cell culture conditions, mouse embryonic fibroblasts (MEFs) derived from ASK1 KO mice show no differences in either MAPK signaling or osteogenic or chondrogenic differentiation when compared with wild-type (WT) MEFs. However, when cultured with stress activators, H2O2 or staurosporine, the KO cells show enhanced survival, an associated decrease in the activation of proteins involved in death signaling pathways and a reduction in markers of terminal differentiation. Furthermore, in both WT mice treated with the ASK1 inhibitor, NQDI-1, and ASK1 KO mice endochondral bone formation was increased in an ectopic ossification model. These findings highlight a previously unrealized role for ASK1 in regulating endochondral bone formation. Inhibition of ASK1 has clinical potential to treat fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and slowing hypertrophy.

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28 citations in Scopus

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Web of Science research areas
Cell Biology
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