Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation

DMM Disease Models and Mechanisms - Tập 3 Số 3-4 - Trang 224-235 - 2010
Nathalie Ortéga1,2, Ke Wang3,4,4, Napoleone Ferrara5, Zena Werb1, Thiennu H. Vu6,3
1Department of Anatomy
2Present address: IPBS, CNRS UMR5089, Laboratoire de Biologie Vasculaire, 31077 Toulouse Cedex, France
3Lung Biology Center, University of California, San Francisco, CA 94143, USA
4Present address: Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin 130041, People's Republic of China
5Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
6Department of Medicine and

Tóm tắt

SUMMARYLong bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9−/− growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9−/− phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9−/− growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.

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DMM Disease Models and Mechanisms

Tập 3 Số 3-4

224-235

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