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 macrophag e infiltration and high levels of matrix metalloproteinases (MMPs) MMP-3 an d MMP-7. We developed a model system in which disc tissue or isolated chond rocytes from wild-type or MMP-null mice were cocultured with peritoneal mac rophages and used this system to investigate the role of MMPs and chondrocy te/macrophage interactions in disc resorption, We observed a marked enhance ment of MMP-3 protein and mRNA in chondrocytes after exposure to macrophage s. Chondrocytic MMP-3, but not MMP-7, was required for disc resorption, as determined by assaying for a reduction in wet weight and proteoglycan conte nt after 3 days of coculture, Surprisingly, chondrocyte MMP-3 was required for the generation of a macrophage chemoattractant and the subsequent infil tration of the disc tissue by proteolytically active macrophages. We conclu de that macrophage induction of chondrocyte MMP-3 plays a major role in dis c resorption by mechanisms that include the generation of a bioactive macro phage chemoattractant.