TY - JOUR
T1 - MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage
T2 - a critical process in skeletal growth
AU - Holmbeck, Kenn
AU - Bianco, Paolo
AU - Chrysovergis, Kali
AU - Yamada, Susan
AU - Birkedal-Hansen, Henning
PY - 2003/11/10
Y1 - 2003/11/10
N2 - Skeletal tissues develop either by intramembranous ossification, where bone is formed within a soft connective tissue, or by endochondral ossification. The latter proceeds via cartilage anlagen, which through hypertrophy, mineralization, and partial resorption ultimately provides scaffolding for bone formation. Here, we describe a novel and essential mechanism governing remodeling of unmineralized cartilage anlagen into membranous bone, as well as tendons and ligaments. Membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent dissolution of unmineralized cartilages, coupled with apoptosis of nonhypertrophic chondrocytes, mediates remodeling of these cartilages into other tissues. The MT1-MMP deficiency disrupts this process and uncouples apoptotic demise of chondrocytes and cartilage degradation, resulting in the persistence of "ghost" cartilages with adverse effects on skeletal integrity. Some cells entrapped in these ghost cartilages escape apoptosis, maintain DNA synthesis, and assume phenotypes normally found in the tissues replacing unmineralized cartilages. The coordinated apoptosis and matrix metalloproteinase-directed cartilage dissolution is akin to metamorphosis and may thus represent its evolutionary legacy in mammals.
AB - Skeletal tissues develop either by intramembranous ossification, where bone is formed within a soft connective tissue, or by endochondral ossification. The latter proceeds via cartilage anlagen, which through hypertrophy, mineralization, and partial resorption ultimately provides scaffolding for bone formation. Here, we describe a novel and essential mechanism governing remodeling of unmineralized cartilage anlagen into membranous bone, as well as tendons and ligaments. Membrane-type 1 matrix metalloproteinase (MT1-MMP)-dependent dissolution of unmineralized cartilages, coupled with apoptosis of nonhypertrophic chondrocytes, mediates remodeling of these cartilages into other tissues. The MT1-MMP deficiency disrupts this process and uncouples apoptotic demise of chondrocytes and cartilage degradation, resulting in the persistence of "ghost" cartilages with adverse effects on skeletal integrity. Some cells entrapped in these ghost cartilages escape apoptosis, maintain DNA synthesis, and assume phenotypes normally found in the tissues replacing unmineralized cartilages. The coordinated apoptosis and matrix metalloproteinase-directed cartilage dissolution is akin to metamorphosis and may thus represent its evolutionary legacy in mammals.
KW - Animals
KW - Apoptosis/genetics
KW - Bone Remodeling/genetics
KW - Bone and Bones/cytology
KW - Cartilage/cytology
KW - Cell Lineage/genetics
KW - Chondrocytes/cytology
KW - Connective Tissue/embryology
KW - Gene Expression Regulation, Developmental/genetics
KW - Matrix Metalloproteinase 14
KW - Matrix Metalloproteinases, Membrane-Associated
KW - Metalloendopeptidases/deficiency
KW - Metamorphosis, Biological/genetics
KW - Mice
KW - Mice, Knockout
KW - Osteogenesis/genetics
KW - Skull/abnormalities
U2 - 10.1083/jcb.200307061
DO - 10.1083/jcb.200307061
M3 - Journal article
C2 - 14610065
SN - 0021-9525
VL - 163
SP - 661
EP - 671
JO - The Journal of Cell Biology
JF - The Journal of Cell Biology
IS - 3
ER -