Decreased Chondrocyte Proliferation and Dysregulated Apoptosis in the Cartilage Growth Plate Are Key Features of a Murine Model of Epiphyseal Dysplasia Caused by a Matn3 Mutation

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2007 May 23

PMID 17517694

Citations 43

Authors

Matthew P Leighton

Seema Nundlall

Tobias Starborg

Roger S Meadows

Farhana Suleman

Lynette Knowles

Raimund Wagener

David J Thornton

Karl E Kadler

Raymond P Boot-Handford

Michael D Briggs

Affiliations

Soon will be listed here.

Abstract

Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.

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References

Spranger J . Bone dysplasia 'families'. Pathol Immunopathol Res. 1988; 7(1-2):76-80. DOI: 10.1159/000157098. View

Mazzarella R, Srinivasan M, Haugejorden S, Green M . ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase. J Biol Chem. 1990; 265(2):1094-101. View

Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Sommarin Y . Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem. 1992; 267(9):6132-6. View

Braun T, Rudnicki M, Arnold H, Jaenisch R . Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Cell. 1992; 71(3):369-82. DOI: 10.1016/0092-8674(92)90507-9. View

Kremer J, Mastronarde D, McIntosh J . Computer visualization of three-dimensional image data using IMOD. J Struct Biol. 1996; 116(1):71-6. DOI: 10.1006/jsbi.1996.0013. View

Zenmyo M, Komiya S, Kawabata R, Sasaguri Y, Inoue A, Morimatsu M . Morphological and biochemical evidence for apoptosis in the terminal hypertrophic chondrocytes of the growth plate. J Pathol. 1996; 180(4):430-3. DOI: 10.1002/(SICI)1096-9896(199612)180:4<430::AID-PATH691>3.0.CO;2-H. View

Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot R, Remotti H . CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998; 12(7):982-95. PMC: 316680. DOI: 10.1101/gad.12.7.982. View

Wu J, Eyre D . Matrilin-3 forms disulfide-linked oligomers with matrilin-1 in bovine epiphyseal cartilage. J Biol Chem. 1998; 273(28):17433-8. DOI: 10.1074/jbc.273.28.17433. View

. International nomenclature and classification of the osteochondrodysplasias (1997). International Working Group on Constitutional Diseases of Bone. Am J Med Genet. 1998; 79(5):376-82. DOI: 10.1002/(sici)1096-8628(19981012)79:5<376::aid-ajmg9>3.0.co;2-h. View

10.

Li C, Chen L, Iwata T, Kitagawa M, Fu X, Deng C . A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum Mol Genet. 1999; 8(1):35-44. DOI: 10.1093/hmg/8.1.35. View

11.

Hecht J, Montufar-Solis D, Decker G, Lawler J, Daniels K, Duke P . Retention of cartilage oligomeric matrix protein (COMP) and cell death in redifferentiated pseudoachondroplasia chondrocytes. Matrix Biol. 1999; 17(8-9):625-33. DOI: 10.1016/s0945-053x(98)90113-5. View

12.

Kaufman R . Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999; 13(10):1211-33. DOI: 10.1101/gad.13.10.1211. View

13.

Aszodi A, Bateman J, Hirsch E, Baranyi M, Hunziker E, Hauser N . Normal skeletal development of mice lacking matrilin 1: redundant function of matrilins in cartilage?. Mol Cell Biol. 1999; 19(11):7841-5. PMC: 84857. DOI: 10.1128/MCB.19.11.7841. View

14.

Hecht J, Hayes E, Haynes R, Cole W . COMP mutations, chondrocyte function and cartilage matrix. Matrix Biol. 2005; 23(8):525-33. DOI: 10.1016/j.matbio.2004.09.006. View

15.

Kennedy J, Jackson G, Ramsden S, Taylor J, Newman W, Wright M . COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. Eur J Hum Genet. 2005; 13(5):547-55. PMC: 2673054. DOI: 10.1038/sj.ejhg.5201374. View

16.

Loughlin J . The genetic epidemiology of human primary osteoarthritis: current status. Expert Rev Mol Med. 2005; 7(9):1-12. DOI: 10.1017/S1462399405009257. View

17.

Wagener R, Ehlen H, Ko Y, Kobbe B, Mann H, Sengle G . The matrilins--adaptor proteins in the extracellular matrix. FEBS Lett. 2005; 579(15):3323-9. DOI: 10.1016/j.febslet.2005.03.018. View

18.

Maeda K, Nakashima E, Horikoshi T, Mabuchi A, Ikegawa S . Mutation in the von Willebrand factor-A domain is not a prerequisite for the MATN3 mutation in multiple epiphyseal dysplasia. Am J Med Genet A. 2005; 136(3):285-6. DOI: 10.1002/ajmg.a.30832. View

19.

OTTEN C, Wagener R, Paulsson M, Zaucke F . Matrilin-3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not. J Med Genet. 2005; 42(10):774-9. PMC: 1735938. DOI: 10.1136/jmg.2004.029462. View

20.

Budde B, Blumbach K, Ylostalo J, Zaucke F, Ehlen H, Wagener R . Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX. Mol Cell Biol. 2005; 25(23):10465-78. PMC: 1291247. DOI: 10.1128/MCB.25.23.10465-10478.2005. View