Cleavage Site Specificity of Cathepsin K toward Cartilage Proteoglycans and Protease Complex Formation

Hou, Wu-Shiun; Li, Zhenqiang; Büttner, Frank; Bartnik, Eckart; Brὂmme, Dieter

doi:10.1515/bc.2003.100

Cited by 79 publications

(67 citation statements)

References 32 publications

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“…However, only a subset of GAGs allowed the generation of collagenolytically active complexes. Interestingly, these were GAGs that are predominantly expressed in bone and cartilage (chondroitin sulfates and keratan sulfates), the sites of the probably main biological activity of cathepsin K. These GAGs are easily liberated by cathepsin activities from aggregan aggregates or cartilage and can subsequently form complexes with cathepsin K (39). Other GAGs such as dermatan sulfate, heparan sulfate, and heparin are also able to form stable complexes but do not support any collagenase activity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Yasuda

et al. 2004

Journal of Biological Chemistry

212

210

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Cathepsin K, a lysosomal papain-like cysteine protease, forms collagenolytically highly active complexes with chondroitin sulfate and represents the most potent mammalian collagenase. Here we demonstrate that complex formation with glycosaminoglycans (GAGs) is unique for cathepsin K among human papain-like cysteine proteases and that different GAGs compete for the binding to cathepsin K. GAGs predominantly expressed in bone and cartilage, such as chondroitin and keratan sulfates, enhance the collagenolytic activity of cathepsin K, whereas dermatan, heparan sulfate, and heparin selectively inhibit this activity. Moreover, GAGs potently inhibit the collagenase activity of other cysteine proteases such as cathepsins L and S at 37°C. Along this line MMP1-generated collagen fragments in the presence of GAGs are stable against further degradation at 28°C by all cathepsins but cathepsin K, whereas thermal destabilization at 37°C renders the fragments accessible to all cathepsins. These results suggest a novel mechanism for the regulation of matrix protein degradation by GAGs. It further implies that cathepsin K represents the only lysosomal collagenolytic activity under physiologically relevant conditions.Controlled degradation of collagen is observed in bone remodeling, wound healing, angiogenesis, and during organ development (1-3). On the other hand excessive collagen degradation leads to pathological phenotypes such as osteoporosis (4), various forms of arthritis (5), or aneurysms of blood vessels (6), or it is characteristic for tumor invasion (7). However, triple helical collagens, in particular type I and II collagens, are highly resistant to general proteolysis and require specific proteases for their degradation. Known mammalian collagenolytic activities include members of the matrix metalloprotease family such as MMP-1, -2, -8, -13, and -14 (8), the serine protease, human neutrophil elastase (9), and thiol-dependent cathepsins (1). Collagenases of the MMP family cleave triple helical collagen at a specific single site and release 3 ⁄4 and 1 ⁄4 fragments. Similar to MMPs, human neutrophil elastase generates 3 ⁄4 fragments from type I collagen but is unable to degrade type II collagen (9). Lysosomal cysteine proteases such as cathepsins L and B have also been discussed as collagenolytic activities, but these data were mostly based on inhibitor experiments in cell extracts or on early preparations of cathepsins, which may not have excluded contaminating activities (10 -13). Thorough enzymatic studies suggested that cathepsins B and L primarily cleave in the non-helical telopeptide extensions of collagens (14, 15). A truly triple helical collagenase activity is found in cathepsin K, which is predominantly expressed in osteoclasts and to a lower degree in various other cell types including fibroblasts (16 -19). It was demonstrated that cathepsin K, similar to the bacterial Clostridium collagenase, cleaves at multiple sites within the triple helical region of types I and II collagens (20,21). The biological relevan...

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Section: Discussionmentioning

confidence: 99%

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Yasuda

et al. 2004

Journal of Biological Chemistry

212

210

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“…In the P1 position, the substrate preference is similar in cathepsin L and K with a preference for amino acids with a hydrophilic side chain such as Arg, Lys, Gln, or Met (31,67,68), although amino acids with short side chains such as Gly or Ser can also be allowed (69,70 Both cathepsin K and L are expressed in osteoclasts (71), although cathepsin K is more abundant than cathepsin L at the mRNA (72,73) and activity (52) levels. Our RT-PCR and Western blot analysis on bone extracts and immunohistochemistry on bone tissue sections clearly indicated a higher expression of cathepsin K versus L in trabecular osteoclasts and, moreover, indicated that the majority of cathepsin K protein was processed to the active form and co-localized with TRAP in osteoclasts, whereas the majority of cathepsin L was present as the inactive precursor form and did not co-localize to a significant extent with TRAP in osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Excision of a Repressive Loop Domain in Tartrate-resistant Acid Phosphatase by Cathepsin K in Osteoclasts

Ljusberg¹,

Wang²,

Lång³

et al. 2005

Journal of Biological Chemistry

126

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Tartrate-resistant acid phosphatase (TRAP) is a metallophosphoesterase participating in osteoclast-mediated bone turnover. Activation of TRAP is associated with the redox state of the di-iron metal center as well as with limited proteolytic cleavage in an exposed loop domain. The cysteine proteinases cathepsin B, L, K, and S as well as the matrix metalloproteinase-2, -9, -13, and -14 are expressed by osteoclasts and/or other bone cells and have been implicated in the turnover of bone and cartilage. To identify proteases that could act as activators of TRAP in bone, we report here that cathepsins K and L, in contrast to the matrix metalloproteinases, efficiently cleaved and activated recombinant TRAP in vitro. Activation of TRAP by cathepsin K/L was because of increases in catalytic activity, substrate affinity, and sensitivity to reductants. Processing by cathepsin K occurred sequentially by an initial excision of the loop peptide Gly Tartrate-resistant acid phosphatase (TRAP), 1 also known as type 5 acid phosphatase (EC 3.1.3.2) or uteroferrin, belongs to the purple acid phosphatase (PAP) subfamily of the non-heme dinuclear metallophosphatases (1-3). The metals of the catalytic center of all PAPs consist of a common ferric ion and a divalent metal cation in an active enzyme, where mammalian PAPs characteristically contain a redox-active iron in the M(II) site (4 -6).The TRAP enzyme is abundantly expressed by bone-resorbing cells, osteoclasts, and certain subpopulations of monocytes/ macrophages and dendritic cells (7-10). The precise role of osteoclastic TRAP is not fully understood, but studies on TRAP knock-out mice showed disturbed endochondral ossification with decreased resorptive activity of osteoclasts (11, 12), whereas overexpression of TRAP was associated with increased bone turnover (10). Different functions have been suggested for TRAP, e.g. as an osteopontin phosphatase (13-15), generation of reactive oxygen species (16 -19), iron transport (20 -24), and as a growth/differentiation factor for hematopoietic (25) and osteoblastic (26) cells.Mammalian PAPs are synthesized as 35-37-kDa monomers but are commonly isolated from tissues as proteolytically cleaved two-subunit forms consisting of a 23-kDa N-terminal domain disulfide-linked to a 16-kDa C-terminal domain. The monomeric form exhibits properties of a proenzyme with low phosphatase activity that is converted to a high activity, twosubunit form upon proteolytic cleavage in the intervening loop domain with either serine proteases, e.g. trypsin or chymotrypsin (27), or members of the cathepsin family (28,29). Mutagenesis studies suggested that proteolysis removes or alters repressive interactions between loop amino acids and active site residues because replacement of Asp 146 of the exposed loop domain with Ala resulted in activation of unproteolyzed TRAP (30).Several lines of evidence indicate a role for cathepsin K in bone resorption. Cathepsin K is highly expressed in osteoclasts near the ruffled border membrane and has been shown to participate i...

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“…Besides collagens, cathepsin K cleaves a variety of other bone-and cartilage resident proteins such as osteonectin, aggrecan, and IGF-1 [22,23].…”

Section: Introductionmentioning

confidence: 99%

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

Atef¹,

Aziz²

2015

J Arthritis

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Cleavage Site Specificity of Cathepsin K toward Cartilage Proteoglycans and Protease Complex Formation

Cited by 79 publications

References 32 publications

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Proteolytic Excision of a Repressive Loop Domain in Tartrate-resistant Acid Phosphatase by Cathepsin K in Osteoclasts

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

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Cleavage Site Specificity of Cathepsin K toward Cartilage Proteoglycans and Protease Complex Formation

Cited by 79 publications

References 32 publications

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Regulation of Collagenase Activities of Human Cathepsins by Glycosaminoglycans

Proteolytic Excision of a Repressive Loop Domain in Tartrate-resistant Acid Phosphatase by Cathepsin K in Osteoclasts

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy

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Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF ÃÂ± Therapy