Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption.
Herniated disc (HD) is a common health problem that is resolved by surgery unless spontaneous resorption occurs. HD tissue contains abundant macrophage infiltration and high levels of matrix metalloproteinases (MMPs) MMP-3 and MMP-7. We developed a model system in which disc tissue or isolated chondrocytes from wild-type or MMP-null mice were cocultured with peritoneal macrophages and used this system to investigate the role of MMPs and chondrocyte/macrophage interactions in disc resorption. We observed a marked enhancement of MMP-3 protein and mRNA in chondrocytes after exposure to macrophages. Chondrocytic MMP-3, but not MMP-7, was required for disc resorption, as determined by assaying for a reduction in wet weight and proteoglycan content after 3 days of coculture. Surprisingly, chondrocyte MMP-3 was required for the generation of a macrophage chemoattractant and the subsequent infiltration of the disc tissue by proteolytically active macrophages. We conclude that macrophage induction of chondrocyte MMP-3 plays a major role in disc resorption by mechanisms that include the generation of a bioactive macrophage chemoattractant.
Haro
H
H
Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Crawford
H C
HC
Fingleton
B
B
MacDougall
J R
JR
Shinomiya
K
K
Spengler
D M
DM
Matrisian
L M
LM
D000818:Animals; D015153:Blotting, Western; D002464:Cell Migration Inhibition; D019902:Chondrocytes / Q000166:cytology / Q000201:enzymology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007403:Intervertebral Disc / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007405:Intervertebral Disc Displacement / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7