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Altered endochondral bone development in matrix metalloproteinase 13-deficient mice
Dominique Stickens1, Danielle J Behonick, Nathalie Ortega
1Department of Anatomy and Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143-0452, USA. domi@itsa.ucsf.edu
Development (Cambridge, England)
|November 13, 2004
Summary
Matrix metalloproteinase 13 (MMP13) is essential for bone development. Its absence impairs extracellular matrix remodeling, leading to skeletal growth defects, but these resolve over time.
Area of Science:
- Skeletal Biology
- Extracellular Matrix Biology
- Enzymology
Background:
- Extracellular matrix (ECM) assembly and degradation are vital for bone development.
- Matrix metalloproteinase (MMP) 13 is expressed in growth plate chondrocytes and osteoblasts, suggesting a key role in bone formation and remodeling.
- Mutations in MMP13 are linked to spondyloepimetaphyseal dysplasia.
Purpose of the Study:
- To investigate the role of MMP13 in endochondral bone formation and ECM remodeling.
- To identify the in vivo substrates of MMP13 in cartilage.
- To elucidate the synergistic action of MMP13 with other proteases in bone development.
Main Methods:
- Homologous recombination to generate Mmp13-null mice.
- Conditional inactivation of Mmp13 in chondrocytes and osteoblasts.
- Analysis of skeletal growth plate development, chondrocyte differentiation, and ECM degradation.
- Identification of MMP13 substrates using biochemical and genetic approaches.
Main Results:
- Mmp13 inactivation caused delayed chondrocyte exit from the growth plate and abnormal skeletal development, with phenotypes resolving by 12 weeks.
- Mmp13-null mice exhibited increased and persistent trabecular bone.
- MMP13 degrades collagen type II and aggrecan, acting synergistically with MMP9.
- Mice lacking both MMP13 and MMP9 showed severely impaired endochondral bone formation, with defects in ECM remodeling, chondrocyte survival, vascular recruitment, and bone development.
Conclusions:
- ECM remodeling is a critical rate-limiting step in endochondral bone formation.
- MMP13 is essential for proper cartilage ECM degradation, chondrocyte programmed cell death, angiogenesis, and osteoblast recruitment during skeletal morphogenesis.
- MMP13 and MMP9 cooperate to regulate cartilage ECM degradation and ensure normal bone development.