title: Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis.
abstract: OBJECTIVE
  To correlate the increased collagenase production previously seen in chondrocytes isolated from osteoarthritic (OA) lesions and the expression of cytokines and cytokine receptors.
  
  
  METHODS
  Chondrocytes were isolated from OA cartilage and characterized for synthesis of collagenases, cytokines, and cytokine receptors by Northern and Western blot analyses, RNA protection assay, and flow cytometry.
  
  
  RESULTS
  Chondrocytes located in cartilage proximal to the macroscopic OA lesions bound more tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) compared with chondrocytes isolated from morphologically normal cartilage from the same joint. In response to TNFalpha stimulation, messenger RNA (mRNA) levels for the IL-1 receptor I (IL-1RI), IL-1RII, TNF receptor II (TNFR II), and IL-6 receptor as well as the level of proinflammatory cytokines, such as IL-1alpha, IL-1beta, lymphotoxin beta, TNFalpha, and IL-6, also increased. In contrast, treatment with transforming growth factor beta1 (TGFbeta1) resulted in down-regulation of matrix metalloproteinase 1 (MMP-1) and MMP-13 concomitant with a reduction in the levels of mRNA for IL-1RI, IL-1RII, TNFRI, and TNFRII and proinflammatory cytokine levels. In contrast, the levels of mRNA for TGFbeta receptor I, TGFbeta1, and TGFbeta3 were up-regulated.
  
  
  CONCLUSIONS
  These data show that TGFbeta1 has antagonistic effects upon OA chondrocytes, in contrast to the effects seen with TNFalpha. The cyclical course of OA, where a period of active disease is followed by a period of remission, can be explained by a sequential pattern of cytokine stimulation followed by a feedback inhibition of autocrine cytokine production and cytokine receptor expression, thus affecting collagenase synthesis.
authors.affiliation: Department of Veterans Affairs Medical Center, and University of Tennessee, Memphis 38104, USA.
authors.forename: B V
authors.initials: BV
authors.lastname: Shlopov
authors.forename: M L
authors.initials: ML
authors.lastname: Gumanovskaya
authors.forename: K A
authors.initials: KA
authors.lastname: Hasty
mesh_terms: D000368:Aged; D019898:Autocrine Communication / Q000276:immunology*; D019902:Chondrocytes / Q000201:enzymology* / Q000276:immunology; D017364:Collagenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1