The Journal of Experimental Medicine
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Published online 18 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/9/789/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 6, September 18, 2000 789-800

Original Article

Regulation of Elastinolytic Cysteine Proteinase Activity in Normal and Cathepsin K–Deficient Human Macrophages

Antonello Punturieria, Sergey Filippova, Edward Allena, Ingrid Carasb, Richard Murrayb, Vivek Reddya, and Stephen J. Weissa

a Department of Internal Medicine and the University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109
b Eos Biotechnology, Incorporated, South San Francisco, California 94080
University of Michigan Comprehensive Cancer Center, 5240 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0640.734-764-0101734-764-0030

sjweiss{at}umich.edu

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.

Key Words: cysteine proteinases • macrophages • cathepsin K • elastinolysis • pycnodysostosis

Abbreviations used in the paper: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; gp, glycoprotein; MDM, monocyte-derived macrophage; TEM, transmission electron microscopy; TPA, tetradecanoylphorbol 13-acetate.

A. Punturieri's present address is Veteran's Affairs Medical Center, 2215 Fuller Rd., Pulmonary Section (111G), Ann Arbor, MI 48109. V. Reddy's present address is Division of Cardiology, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114.

© 2000 The Rockefeller University Press


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