MT1-MMP and type II collagen specify skeletal stem cells and their bone and cartilage progeny

TY - JOUR

T1 - MT1-MMP and type II collagen specify skeletal stem cells and their bone and cartilage progeny

AU - Szabova, Ludmila

AU - Yamada, Susan S

AU - Wimer, Helen F

AU - Chrysovergis, Kaliopi

AU - Ingvarsen, Signe

AU - Behrendt, Niels

AU - Engelholm, Lars H

AU - Holmbeck, Kenn

PY - 2009/11

Y1 - 2009/11

N2 - Skeletal formation is dependent on timely recruitment of skeletal stem cells and their ensuing synthesis and remodeling of the major fibrillar collagens, type I collagen and type II collagen, in bone and cartilage tissues during development and postnatal growth. Loss of the major collagenolytic activity associated with the membrane-type 1 matrix metalloproteinase (MT1-MMP) results in disrupted skeletal development and growth in both cartilage and bone, where MT1-MMP is required for pericellular collagen dissolution. We show here that reconstitution of MT1-MMP activity in the type II collagen-expressing cells of the skeleton rescues not only diminished chondrocyte proliferation, but surprisingly, also results in amelioration of the severe skeletal dysplasia associated with MT1-MMP deficiency through enhanced bone formation. Consistent with this increased bone formation, type II collagen was identified in bone cells and skeletal stem/progenitor cells of wildtype mice. Moreover, bone marrow stromal cells isolated from mice expressing MT1-MMP under the control of the type II collagen promoter in an MT1-MMP-deficient background showed enhanced bone formation in vitro and in vivo compared with cells derived from nontransgenic MT1-MMP-deficient littermates. These observations show that type II collagen is not stringently confined to the chondrocyte but is expressed in skeletal stem/progenitor cells (able to regenerate bone, cartilage, myelosupportive stroma, marrow adipocytes) and in the chondrogenic and osteogenic lineage progeny where collagenolytic activity is a requisite for proper cell and tissue function.

AB - Skeletal formation is dependent on timely recruitment of skeletal stem cells and their ensuing synthesis and remodeling of the major fibrillar collagens, type I collagen and type II collagen, in bone and cartilage tissues during development and postnatal growth. Loss of the major collagenolytic activity associated with the membrane-type 1 matrix metalloproteinase (MT1-MMP) results in disrupted skeletal development and growth in both cartilage and bone, where MT1-MMP is required for pericellular collagen dissolution. We show here that reconstitution of MT1-MMP activity in the type II collagen-expressing cells of the skeleton rescues not only diminished chondrocyte proliferation, but surprisingly, also results in amelioration of the severe skeletal dysplasia associated with MT1-MMP deficiency through enhanced bone formation. Consistent with this increased bone formation, type II collagen was identified in bone cells and skeletal stem/progenitor cells of wildtype mice. Moreover, bone marrow stromal cells isolated from mice expressing MT1-MMP under the control of the type II collagen promoter in an MT1-MMP-deficient background showed enhanced bone formation in vitro and in vivo compared with cells derived from nontransgenic MT1-MMP-deficient littermates. These observations show that type II collagen is not stringently confined to the chondrocyte but is expressed in skeletal stem/progenitor cells (able to regenerate bone, cartilage, myelosupportive stroma, marrow adipocytes) and in the chondrogenic and osteogenic lineage progeny where collagenolytic activity is a requisite for proper cell and tissue function.

KW - Adipocytes

KW - Animals

KW - Body Weight

KW - Bone Marrow

KW - Bone and Bones

KW - Cartilage

KW - Cell Lineage

KW - Cell Proliferation

KW - Chondrocytes

KW - Collagen Type II

KW - Matrix Metalloproteinase 14

KW - Mice

KW - Organ Specificity

KW - Osteogenesis

KW - Rats

KW - Stem Cells

KW - Survival Analysis

KW - Transgenes

KW - Weight Gain

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1359/jbmr.090510

DO - 10.1359/jbmr.090510

M3 - Journal article

C2 - 19419317

SN - 0884-0431

VL - 24

SP - 1905

EP - 1916

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 11

ER -