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Vol. 16, Issue 6, 3028-3039, June 2005

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Galectin-3 Is a Downstream Regulator of Matrix Metalloproteinase-9 Function during Endochondral Bone Formation

Nathalie Ortega ^* , Danielle J. Behonick ^*, Céline Colnot , Douglas N.W. Cooper ^* , and Zena Werb ^*

^* Department of Anatomy, University of California–San Francisco, San Francisco, CA 94143; Department of Orthopaedic Surgery, University of California–San Francisco, San Francisco, CA 94143; and Department of Langley Porter Psychiatric Institute, University of California–San Francisco, San Francisco, CA 94143

Submitted December 27, 2004; Revised March 16, 2005; Accepted March 23, 2005
Monitoring Editor: Jean Schwarzbauer

Endochondral bone formation is characterized by the progressive replacement of a cartilage anlagen by bone at the growth plate with a tight balance between the rates of chondrocyte proliferation, differentiation, and cell death. Deficiency of matrix metalloproteinase-9 (MMP-9) leads to an accumulation of late hypertrophic chondrocytes. We found that galectin-3, an in vitro substrate of MMP-9, accumulates in the late hypertrophic chondrocytes and their surrounding extracellular matrix in the expanded hypertrophic cartilage zone. Treatment of wild-type embryonic metatarsals in culture with full-length galectin-3, but not galectin-3 cleaved by MMP-9, mimicked the embryonic phenotype of Mmp-9 null mice, with an increased hypertrophic zone and decreased osteoclast recruitment. These results indicate that extracellular galectin-3 could be an endogenous substrate of MMP-9 that acts downstream to regulate hypertrophic chondrocyte death and osteoclast recruitment during endochondral bone formation. Thus, the disruption of growth plate homeostasis in Mmp-9 null mice links galectin-3 and MMP-9 in the regulation of the clearance of late chondrocytes through regulation of their terminal differentiation.

Abbreviations used: Col2, collagen type II; Col10, collagen type X; CTGF, connective tissue growth factor; ECM, extracellular matrix; HC, hypertrophic chondrocyte(s); MMP, matrix metalloproteinase; PECAM, platelet endothelial cell adhesion molecule; TRAP, tartrate-resistant acidic phosphatase; TG2, tissue transglutaminase; MT1-MMP, membrane type 1 matrix metalloproteinase; VEGF, vascular endothelial growth factor.

Present address: IPBS, CNRS UMR 5089, Laboratoire de Biologie Vasculaire, 205 route de Narbonne, 31077 Toulouse Cedex, France.

Address correspondence to: Zena Werb (zena{at}itsa.ucsf.edu).

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