Lefty contributes to the remodeling of extracellular matrix by inhibition of connective tissue growth factor and collagen mRNA expression and increased proteolytic activity in a fibrosarcoma model.
Homeostasis of the extracellular matrix (ECM) of tissues is regulated by controlling deposition and degradation of ECM proteins. The breakdown of ECM is essential in blastocyst implantation and embryonic development, tissue morphogenesis, menstrual shedding, bone formation, tissue resorption after delivery, and tumor growth and invasion. TGF-beta family members are one of the classes of proteins that actively participate in the homeostasis of ECM. Here, we report on the effect of lefty, a novel member of the TGF-beta family, on the homeostasis of extracellular matrix in a fibrosarcoma model. Fibroblastic cells forced to express lefty by retroviral transduction lost their ability to deposit collagen in vivo. This event was associated with down-regulation of the steady-state level of connective tissue growth factor that induces collagen type I mRNA. In addition, lefty transduction significantly decreased collagen type I mRNA expression and simultaneously increased collagenolytic, gelatinolytic, elastolytic, and caseinolytic activities in vivo by the transduced fibroblasts. These findings provide a new insight on the actions of lefty and suggest that this cytokine plays an active role in remodeling of the extracellular matrix in vivo.
Mason
James M
JM
Department of Pathology, North Shore-Long Island Jewish Research Institute and New York University School of Medicine, Manhasset, New York 11030, USA.
Xu
Hao-Peng
HP
Rao
Srinivasa K
SK
Leask
Andrew
A
Barcia
Michele
M
Shan
Jidong
J
Stephenson
Robert
R
Tabibzadeh
Siamak
S
D000818:Animals; D024042:Collagen Type I / Q000235:genetics*; D055513:Connective Tissue Growth Factor; D005109:Extracellular Matrix / Q000378:metabolism*; D005354:Fibrosarcoma / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics*; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D020782:Matrix Metalloproteinases / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000032:analysis*; D016212:Transforming Growth Factor beta / Q000502:physiology*
C526318:CCN2 protein, mouse; D024042:Collagen Type I; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D020782:Matrix Metalloproteinases