Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2644–2654, August 2012
How to Cite
Groma, G., Xin, W., Grskovic, I., Niehoff, A., Brachvogel, B., Paulsson, M. and Zaucke, F. (2012), Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double-deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation. Arthritis & Rheumatism, 64: 2644–2654. doi: 10.1002/art.34435
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 29 FEB 2012 12:47PM EST
- Manuscript Accepted: 9 FEB 2012
- Manuscript Received: 7 MAR 2011
- DFG. Grant Numbers: BR 2304/5-1, WA 1338/2-6, ZA 561/2-1
- Köln Fortune Programme of the Medical Faculty
- University of Cologne
Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.
To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.
At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)–deficient mice.
We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 double-deficient and MMP-13–deficient mice.