Cysteine Cathepsins and the Skeleton

Brὂmme, Dieter

doi:10.1007/s12018-011-9101-y

Cited by 8 publications

(5 citation statements)

References 120 publications

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“…In the colon of Ctsk −/− mice, the levels of collagen IV and the immunostaining intensities with laminin-specific antibodies were significantly higher than in WT animals, suggesting a role for cathepsin K in the remodeling of ECM and basement membrane. The notion of a major task for cathepsin K in ECM turnover can also be deduced from the severe side effects observed in cathepsin K inhibitor treatments, namely skin rashes and fibrotic scleroderma, eventually resulting in the accumulation of collagen fibers (Desmarais et al, 2008, 2009; Brömme, 2011). The basement membrane plays an important role in maintaining intestinal structure and compartmentalization, while it is also involved in various cellular processes such as adhesion, proliferation, and differentiation (Timpl, 1996; Mahoney et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon

Arampatzidou

Schutte²,

Hansson³

et al. 2012

Biological Chemistry

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Cathepsin K has been shown to exhibit antimicrobial and anti-inflammatory activities in the mouse colon. To further elucidate its role, we used Ctsk−/− mice and demonstrated that the absence of cathepsin K was accompanied by elevated protein levels of related cysteine cathepsins (cathepsins B, L, and X) in the colon. In principle, such changes could result in altered subcellular localization; however, the trafficking of cysteine cathepsins was not affected in the colon of Ctsk−/− mice. However, cathepsin K deficiency affected the extracellular matrix constituents, as higher amounts of collagen IV and laminin were observed. Moreover, the localization pattern of the intercellular junction proteins E-cadherin and occludin was altered in the colon of Ctsk−/− mice, suggesting potential impairment of the barrier function. Thus, we used an ex vivo method for assessing the mucus layers and showed that the absence of cathepsin K had no influence on mucus organization and growth. The data of this study support the notion that cathepsin K contributes to intestinal homeostasis and tissue architecture, but the lack of cathepsin K activity is not expected to affect the mucus-depending barrier functions of the mouse colon. These results are important with regard to oral administration of cathepsin K inhibitors that are currently under investigation in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon

Arampatzidou

Schutte²,

Hansson³

et al. 2012

Biological Chemistry

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“…Among the 11 known human cysteine cathepsins, only CatK exerts a triple helical collagen hydrolase activity (3). It is capable of disintegrating compact collagen fibers into fragments and to further solubilize them into soluble peptides (4).…”

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confidence: 99%

Structural basis of collagen fiber degradation by cathepsin K

Aguda¹,

Panwar²,

Du³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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127

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Cathepsin K is the major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation. Despite its key role in bone remodeling and for being a highly sought-after drug target for the treatment of osteoporosis, the mechanism of collagen fiber degradation by cathepsin K remained elusive. Here, we report the structure of a collagenolytically active cathepsin K protein dimer. Cathepsin K is organized into elongated C-shaped protease dimers that reveal a putative collagen-binding interface aided by glycosaminoglycans. Molecular modeling of collagen binding to the dimer indicates the participation of nonactive site amino acid residues, Q21 and Q92, in collagen unfolding. Mutations at these sites as well as perturbation of the dimer protein-protein interface completely inhibit cathepsin-K-mediated fiber degradation without affecting the hydrolysis of gelatin or synthetic peptide. Using scanning electron microscopy, we demonstrate the specific binding of cathepsin K at the edge of the fibrillar gap region of collagen fibers, which suggest initial cleavage events at the N-and C-terminal ends of tropocollagen molecules. Edman degradation analysis of collagen fiber degradation products revealed those initial cleavage sites. We propose that one cathepsin K molecule binds to collagen-bound glycosaminoglycans at the gap region and recruits a second protease molecule that provides an unfolding and cleavage mechanism for triple helical collagen. Removal of collagen-associated glycosaminoglycans prevents cathepsin K binding and subsequently fiber hydrolysis. Cathepsin K dimer and glycosaminoglycan binding sites represent novel targeting sites for the development of nonactive site-directed secondgeneration inhibitors of this important drug target.cathepsin K | collagen | glycosaminoglycan | enzyme mechanism

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“…5,7−9 Odanacatib, an inhibitor of cathepsin K developed by Merck, is currently in phase III clinical trials for the treatment of osteoporosis. 10 Cathepsins are found in the highest concentration in cellular lysosomes, and during cancer progression, they are secreted at an increased rate and degrade the extracellular matrix and basement membrane, which aid in cancer metastasis. 5 Small molecule inhibitors of cathepsin L have been previously identified (Figure 1), including azapenone (I), 11 cyanamide derivative (II), 12 and a purine nitrile analogue (III), 13 as well as amino acid-based molecules including an oxocarbazate analogue (IV) 14 and an epoxide derivative (V).…”

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confidence: 99%

“…There are five classes of proteases including matrix metalloproteases (MMPs), cysteine proteases, serine proteases, aspartic proteases, and threonine proteases, which catalyze the hydrolysis of peptide bonds. , Because of their function in many disease states, including cancer metastasis and cardiovascular disease, proteases have become well-investigated therapeutic targets. − Cysteine protease cathepsins, members of the papain family, have recently been validated as an important enzymatic class to target in cancer research. ,, In this family, there are 11 cathepsin enzymes known to date in humans: B, C, F, H, K, L, O, S, V, W, and X. ,− Odanacatib, an inhibitor of cathepsin K developed by Merck, is currently in phase III clinical trials for the treatment of osteoporosis . Cathepsins are found in the highest concentration in cellular lysosomes, and during cancer progression, they are secreted at an increased rate and degrade the extracellular matrix and basement membrane, which aid in cancer metastasis .…”

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confidence: 99%

Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

Song

Jones

Kumar

et al. 2012

ACS Med. Chem. Lett.

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A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC 50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC 50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC 50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure−activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L.

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Cysteine Cathepsins and the Skeleton

Cited by 8 publications

References 120 publications

Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon

Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon

Structural basis of collagen fiber degradation by cathepsin K

Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

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