Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages.
Human macrophages mediate the dissolution of elastic lamina by mobilizing tissue-destructive cysteine proteinases. While macrophage-mediated elastin degradation has been linked to the expression of cathepsins L and S, these cells also express cathepsin K, a new member of the cysteine proteinase family whose elastinolytic potential exceeds that of all known elastases. To determine the relative role of cathepsin K in elastinolysis, monocytes were differentiated under conditions in which they recapitulated a gene expression profile similar to that observed at sites of tissue damage in vivo. After a 12-d culture period, monocyte-derived macrophages (MDMs) expressed cathepsin K in tandem with cathepsins L and S. Though cysteine proteinases are acidophilic and normally confined to the lysosomal network, MDMs secreted cathepsin K extracellularly in concert with cathepsins L and S. Simultaneously, MDMs increased the expression of vacuolar-type H(+)-ATPase components, acidified the pericellular milieu, and maintained extracellular cathepsin K in an active form. MDMs from a cathepsin K-deficient individual, however, retained the ability to express, process, and secrete cathepsins L and S, and displayed normal elastin-degrading activity. Thus, matrix-destructive MDMs exteriorize a complex mix of proteolytic cysteine proteinases, but maintain full elastinolytic potential in the absence of cathepsin K by mobilizing cathepsins L and S.
Punturieri
A
A
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Filippov
S
S
Allen
E
E
Caras
I
I
Murray
R
R
Reddy
V
V
Weiss
S J
SJ
D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000201:enzymology* / Q000648:ultrastructure; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; D002402:Cathepsin D; D006180:Proton-Translocating ATPases