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Dieter Brömme - One of the best experts on this subject based on the ideXlab platform.
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structural basis of collagen fiber degradation by Cathepsin K
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: A Aguda, Preety Panwar, Xin Du, Nham T Nguyen, Gary D Brayer, Dieter BrömmeAbstract: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 second-generation inhibitors of this important drug target.
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The effect of Cathepsin K deficiency on airway development and TGF-β1 degradation
Respiratory Research, 2011Co-Authors: Dongwei Zhang, Paul Saftig, Ekkehard Weber, Nelson Leung, Dieter BrömmeAbstract:BacKground Cathepsin K, a cysteine protease predominantly expressed in osteoclasts, is a major drug target for the treatment of osteoporosis. Recent findings, however, indicate that Cathepsin K is also involved in non-sKeletal metabolism. The development of fibrotic phenotypes in lung and sKin is a concern for Cathepsin K inhibitors presently evaluated in clinical trials. Cathepsin K is expressed in lung tissue and has been implicated in lung fibrosis. However, little is Known about the role of Cathepsin K in airway development and its effect on TGF-β1 degradation.
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Potential role of Cathepsin K in the pathophysiology of mucopolysaccharidoses.
Journal of pediatric rehabilitation medicine, 2010Co-Authors: Susan Wilson, Dieter BrömmeAbstract:Cathepsin K, a papain-liKe cysteine protease, is highly expressed in osteoclasts and plays a critical role in bone resorption. Dysfunction of the enzyme leads to various sKeletal abnormalities. The recent Knowledge that the collagenolytic activity of Cathepsin K depends on interactions with bone and cartilage-resident glycosaminoglycans (GAGs) may shed some light on diseases such as mucopolysaccharidoses (MPSs). MPSs are a group of lysosomal storage diseases characterized by the accumulation of GAGs in tissues including bone. Typical pathological features of these diseases include sKeletal abnormalities such as dysostosis multiplex, short stature, and multiple irregularities in bone development. We describe how further investigation of the Cathepsin K/GAG complexes could provide valuable insights into the bone pathology associated with MPS diseases. In this review, we discuss the inhibition of osteoclast function through altered activity of Cathepsin K by GAGs and offer insight into a mechanism for the bone pathology seen in MPS patients.
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Cathepsin K inhibitors for osteoporosis and potential off target effects
Expert Opinion on Investigational Drugs, 2009Co-Authors: Dieter Brömme, Fabien LecailleAbstract:Cathepsin K is a highly potent collagenase and the predominant papain-liKe cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable Cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of Cathepsin K research and discuss the current development of Cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-ta...
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Cathepsin K inhibitors for osteoporosis and potential off-target effects
Expert Opinion on Investigational Drugs, 2009Co-Authors: Dieter Brömme, Fabien LecailleAbstract:Cathepsin K is a highly potent collagenase and the predominant papain-liKe cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable Cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of Cathepsin K research and discuss the current development of Cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-target effects of Cathepsin K inhibition and alternative applications of Cathepsin K inhibitors in arthritis, atherosclerosis, blood pressure regulation, obesity and cancer.
Sreejayan Nair - One of the best experts on this subject based on the ideXlab platform.
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Cardiomyocyte-specific disruption of Cathepsin K protects against doxorubicin-induced cardiotoxicity
Cell Death and Disease, 2018Co-Authors: Karin E. Bornfeldt, Sreejayan NairAbstract:The lysosomal cysteine protease Cathepsin K is elevated in humans and animal models of heart failure. Our recent studies show that whole-body deletion of Cathepsin K protects mice against cardiac dysfunction. Whether this is attributable to a direct effect on cardiomyocytes or is a consequence of the global metabolic alterations associated with Cathepsin K deletion is unKnown. To determine the role of Cathepsin K in cardiomyocytes, we developed a cardiomyocyte-specific Cathepsin K-deficient mouse model and tested the hypothesis that ablation of Cathepsin K in cardiomyocytes would ameliorate the cardiotoxic side-effects of the anticancer drug doxorubicin. We used an α-myosin heavy chain promoter to drive expression of Cre, which resulted in over 80% reduction in protein and mRNA levels of cardiac Cathepsin K at baseline. Four-month-old control (Myh-Cre-; CtsK fl/fl) and Cathepsin K KnocKout (Myh-Cre+; CtsK fl/fl) mice received intraperitoneal injections of doxorubicin or vehicle, 1 weeK following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca2+-handling were evaluated. Control mice treated with doxorubicin exhibited a marKed increase in cardiac Cathepsin K, which was associated with an impairment in cardiac structure and function, evidenced as an increase in end-systolic and end-diastolic diameters, decreased fractional shortening and wall thicKness, disruption in cardiac sarcomere and microfilaments and impaired intracellular Ca2+ homeostasis. In contrast, the aforementioned cardiotoxic effects of doxorubicin were attenuated or reversed in mice lacKing cardiac Cathepsin K. Mechanistically, Cathepsin K-deficiency reconciled the disturbance in cardiac energy homeostasis and attenuated NF-κB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease.
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correction cardiomyocyte specific disruption of Cathepsin K protects against doxorubicin induced cardiotoxicity
Cell Death and Disease, 2018Co-Authors: Karin E. Bornfeldt, Sreejayan NairAbstract:The lysosomal cysteine protease Cathepsin K is elevated in humans and animal models of heart failure. Our recent studies show that whole-body deletion of Cathepsin K protects mice against cardiac dysfunction. Whether this is attributable to a direct effect on cardiomyocytes or is a consequence of the global metabolic alterations associated with Cathepsin K deletion is unKnown. To determine the role of Cathepsin K in cardiomyocytes, we developed a cardiomyocyte-specific Cathepsin K-deficient mouse model and tested the hypothesis that ablation of Cathepsin K in cardiomyocytes would ameliorate the cardiotoxic side-effects of the anticancer drug doxorubicin. We used an α-myosin heavy chain promoter to drive expression of Cre, which resulted in over 80% reduction in protein and mRNA levels of cardiac Cathepsin K at baseline. Four-month-old control (Myh-Cre-; CtsK fl/fl) and Cathepsin K KnocKout (Myh-Cre+; CtsK fl/fl) mice received intraperitoneal injections of doxorubicin or vehicle, 1 weeK following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca2+-handling were evaluated. Control mice treated with doxorubicin exhibited a marKed increase in cardiac Cathepsin K, which was associated with an impairment in cardiac structure and function, evidenced as an increase in end-systolic and end-diastolic diameters, decreased fractional shortening and wall thicKness, disruption in cardiac sarcomere and microfilaments and impaired intracellular Ca2+ homeostasis. In contrast, the aforementioned cardiotoxic effects of doxorubicin were attenuated or reversed in mice lacKing cardiac Cathepsin K. Mechanistically, Cathepsin K-deficiency reconciled the disturbance in cardiac energy homeostasis and attenuated NF-κB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease.
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Cathepsin K KnocKout protects against cardiac dysfunction in diabetic mice
Scientific Reports, 2017Co-Authors: Olivia Rogers, Travis E. Brown, Sreejayan NairAbstract:Diabetes is a major risK factor for cardiovascular disease and the lysosomal cysteine protease Cathepsin K plays a critical role in cardiac pathophysiology. To expand upon our previous findings, we tested the hypothesis that, KnocKout of Cathepsin K protects against diabetes-associated cardiac anomalies. Wild-type and Cathepsin K KnocKout mice were rendered diabetic by streptozotocin (STZ) injections. Body weight, organ mass, fasting blood glucose, energy expenditure, cardiac geometry and function, cardiac histomorphology, glutathione levels and protein levels of Cathepsin K and those associated with Ca2+ handling, calcineurin/NFAT signaling, insulin signaling, cardiac apoptosis and fibrosis were determined. STZ-induced diabetic mice exhibited distinct cardiac dysfunction, dampened intracellular calcium handling, alterations in cardiac morphology, and elevated cardiomyocyte apoptosis, which were mitigated in the Cathepsin K KnocKout mice. Additionally, Cathepsin K KnocKout mice attenuated cardiac oxidative stress and calcineurin/NFAT signaling in diabetic mice. In cultured H9c2 myoblasts, pharmacological inhibition of Cathepsin K, or treatment with calcineurin inhibitor rescued cells from high-glucose triggered oxidative stress and apoptosis. Therefore, Cathepsin K may represent a potential target in treating diabetes-associated cardiac dysfunction.
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Cathepsin K KnocKout alleviates aging-induced cardiac dysfunction
Aging Cell, 2015Co-Authors: Timothy J. Robinson, Sreejayan NairAbstract:Aging is a major risK factor for cardiovascular disease. It has previously been shown that protein levels of Cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of Cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that Cathepsin K KnocKout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca2+ properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thicKness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca2+ release compared to young (6-month-old) mice, which were attenuated in the Cathepsin K KnocKout mice. Cellular marKers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-Cathepsin K KnocKout mice compared to their wild-type counterpart. Mechanistically, Cathepsin K KnocKout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of Cathepsin K blocKed the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that Cathepsin K KnocKout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis.
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Cathepsin K KnocKout Alleviates Pressure Overload–Induced Cardiac Hypertrophy
Hypertension, 2013Co-Authors: Xihui Xu, Adam J. Chicco, Sreejayan NairAbstract:Evidence from human and animal studies has documented elevated levels of lysosomal cysteine protease Cathepsin K in failing hearts. Here, we hypothesized that ablation of Cathepsin K mitigates pressure overload–induced cardiac hypertrophy. Cathepsin K KnocKout mice and their wild-type littermates were subjected to abdominal aortic constriction, resulting in cardiac remodeling (heart weight, cardiomyocyte size, left ventricular wall thicKness, and end diastolic and end systolic dimensions) and decreased fractional shortening, the effects of which were significantly attenuated or ablated by Cathepsin K KnocKout. Pressure overload dampened cardiomyocyte contractile function along with decreased resting Ca2+ levels and delayed Ca2+ clearance, which were partly resolved by Cathepsin K KnocKout. Cardiac mammalian target of rapamycin and extracellular signal-regulated Kinases (ERK) signaling cascades were upregulated by pressure overload, the effects of which were attenuated by Cathepsin K KnocKout. In cultured H9c2 myoblast cells, silencing of Cathepsin K blunted, whereas Cathepsin K transfection mimicKed phenylephrine–induced hypertrophic response, along with elevated phosphorylation of mammalian target of rapamycin and ERK. In addition, Cathepsin K protein levels were marKedly elevated in human hearts of end-stage dilated cardiomyopathy. Collectively, our data suggest that Cathepsin K ablation mitigates pressure overload–induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways.
Zhenqiang Li - One of the best experts on this subject based on the ideXlab platform.
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the crystal and molecular structures of a Cathepsin K chondroitin sulfate complex
Journal of Molecular Biology, 2008Co-Authors: Zhenqiang Li, Dieter Brömme, Martin Kienetz, M M Cherney, M N G JamesAbstract:Abstract Cathepsin K is the major collagenolytic enzyme produced by bone-resorbing osteoclasts. We showed earlier that the unique triple-helical collagen-degrading activity of Cathepsin K depends on the formation of complexes with bone-or cartilage-resident glycosaminoglycans, such as chondroitin 4-sulfate (C4-S). Here, we describe the crystal structure of a 1: n complex of Cathepsin K:C4-S inhibited by E64 at a resolution of 1.8 A. The overall structure reveals an unusual “beads-on-a-string”-liKe organization. Multiple Cathepsin K molecules bind specifically to a single cosine curve-shaped strand of C4-S with each Cathepsin K molecule interacting with three disaccharide residues of C4-S. One of the more important sets of interactions comes from a single turn of helix close to the N terminus of the proteinase containing a basic amino acid triplet (Arg8-Lys9-Lys10) that forms multiple hydrogen bonds either to the caboxylate or to the 4-sulfate groups of C4-S. Altogether, the binding sites with C4-S are located in the R-domain of Cathepsin K and are distant from its active site. This explains why the general proteolytic activity of Cathepsin K is not affected by the binding of chondroitin sulfate. Biochemical analyses of Cathepsin K and C4-S mixtures support the presence of a 1: n complex in solution; a dissociation constant, K d , of about 10 nM was determined for the interaction between Cathepsin K and C4-S.
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Selective Inhibition of the Collagenase Activity of Cathepsin K
Journal of Biological Chemistry, 2007Co-Authors: Jana Selent, Zhenqiang Li, Jadwiga Kaleta, Gilles Lalmanach, Dieter BrömmeAbstract:Abstract Cathepsin K, the main bone degrading protease, and chondroitin 4-sulfate (C4-S) form a complex with enhanced collagenase activity. In this report, we demonstrate the specific inhibition of the collagenase activity of Cathepsin K by negatively charged polymers without affecting the overall proteolytic activity of the protease. Three different mechanisms to interfere with Cathepsin-catalyzed collagen degradation are discussed: 1) inhibition of the formation of the Cathepsin K/C4-S complex, 2) inhibition of the attachment of C4-S to collagen, and 3) masKing of the collagenase cleavage sites in collagen. By targeting these interaction sites, collagen degradation can be modulated while the non-collagenolytic activities of Cathepsin K remain intact. The main inhibitory effect on collagen degradation is due to the impeding effect on the active Cathepsin K/C4-S complex. Essential structural elements in the inhibitor molecules are negative charges which compete with the sulfate groups of C4-S in the Cathepsin K/C4-S complex. The inhibitory effect can be controlled by length and charge of the polymers. Longer negatively charged polymers (e.g. polyglutamates, oligonucleotides) tend to inhibit all three mechanisms, whereas shorter ones preferentially affect the Cathepsin K/C4-S complex.
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collagenase activity of Cathepsin K depends on complex formation with chondroitin sulfate
Journal of Biological Chemistry, 2002Co-Authors: Zhenqiang Li, Carlos R Escalantetorres, Bruce D Gelb, Dieter BrömmeAbstract:Abstract Bone resorption in balance with bone formation is vital for the maintenance of the sKeleton and is mediated by osteoclasts. Cathepsin K is the predominant protease in osteoclasts that degrades the bulK of the major bone forming organic component, type I collagen. Although the potent collagenase activity of Cathepsin K is well Known, its mechanism of action remains elusive. Here, we report a Cathepsin K-specific complex with chondroitin sulfate, which is essential for the collagenolytic activity of the enzyme. The complex is an oligomer consisting of five Cathepsin K and five chondroitin sulfate molecules. Only the complex exhibits potent triple helical collagen-degrading activity, whereas monomeric Cathepsin K has no collagenase activity. The primary substrate specificity of Cathepsin K is not altered by complex formation, suggesting that the protease-chondroitin sulfate complex primarily facilitates the destabilization and/or the specific binding of the triple helical collagen structure. Inhibition of complex formation leads to the loss of collagenolytic activity but does not impair the proteolytic activity of Cathepsin K toward noncollagenous substrates. The physiological relevance of Cathepsin K complexes is supported by the findings that (i) the content of chondroitin sulfate present in bone and accessible to Cathepsin K activity is sufficient for complex formation and (ii) Y212C, a Cathepsin K mutant that causes pycnodysostosis (a bone sclerosing disorder) and that has no collagenase activity but remains potent as a gelatinase, is unable to form complexes. These findings reveal a novel mechanism of bone collagen degradation and suggest that targeting Cathepsin K complex formation would be an effective and specific treatment for diseases with excessive bone resorption such as osteoporosis.
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Cathepsin K is a critical protease in synovial fibroblast mediated collagen degradation
American Journal of Pathology, 2001Co-Authors: Zhenqiang Li, Ronald E Gordon, Kyle W H Chan, Michael J Klein, Roger N Levy, Martin Keysser, Gernot Keyszer, Dieter BrömmeAbstract:Synovial fibroblasts (SFs) play a critical role in the pathogenesis of rheumatoid arthritis (RA) and are directly involved in joint destruction. Both SF-resident matrix metalloproteases and Cathepsins have been implicated in cartilage degradation although their identities and individual contributions remain unclear. The aims of this study were to investigate the expression of Cathepsin K in SFs, the correlation between Cathepsin K expression and disease severity, and the contribution of Cathepsin K to fibroblast-mediated collagen degradation. Immunostaining of joint specimens of 21 patients revealed high expression of Cathepsin K in SFs in the synovial lining and the stroma of synovial villi, and to a lesser extent in CD68-positive cells of the synovial lining. Cathepsin K-positive SFs were consistently observed at sites of cartilage and bone degradation. Expression levels of Cathepsin K in the sublining and vascularized areas of inflamed synovia showed a highly significant negative correlation with results derived from the Hannover Functional Capacity Questionnaire (r = 0.78, P = 0.003; and r = 0.70, P = 0.012, respectively) as a measure of the severity of RA in individual patients. For comparison, there was no correlation between Hannover Functional Capacity Questionnaire and Cathepsin S whose expression is limited to CD-68-positive macrophage-liKe synoviocytes. The expression of Cathepsin K was also demonstrated in primary cell cultures of RA-SFs. Co-cultures of SFs on cartilage disKs revealed the ability of fibroblast-liKe cells to phagocytose collagen fibrils whose intralysosomal hydrolysis was prevented in the presence of a potent Cathepsin K inhibitor but not by an inhibitor effective against Cathepsins L, B, and S. The selective and critical role of Cathepsin K in articular cartilage and subchondral bone erosion was further corroborated by the finding that Cathepsin K has a potent aggrecan-degrading activity and that Cathepsin K-generated aggrecan cleavage products specifically potentiate the collagenolytic activity of Cathepsin K toward type I and II collagens. This study demonstrates for the first time a critical role of Cathepsin K in cartilage degradation by SFs in RA that is comparable to its well-Known activity in osteoclasts.
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Localization of Rat Cathepsin K in Osteoclasts and Resorption Pits: Inhibition of Bone Resorption and Cathepsin K-Activity by Peptidyl Vinyl Sulfones
Biological Chemistry, 1999Co-Authors: J. M. Kilb, Zhenqiang Li, Alex Lipyansky, V. Breuil, L. S. Stein, J. T. Palmer, David W. Dempster, Dieter BrömmeAbstract:We have localized Cathepsin K in rat osteoclasts and within exposed resorption pits by immuno-fluorescence microscopy. Intracellular staining using an antibody raised against recombinant mouse Cathepsin K was vesicular and uniformly distributed throughout the cell. Confocal microscopy analysis did not reveal an accumulation of Cathepsin K containing vesicles opposing the ruffled border and the resorption lacuna. Exposed resorption pits exhibited a uniform distribution of Cathepsin K, and no differences were observed between the edges and the centers of the pits. The immunostaining of resorption pits with anti-Cathepsin K antibodies demonstrates that the protease is secreted into the sub-osteoclastic compartment. Cathepsin K-specific inhibition using peptidyl vinyl sulfones as selective cysteine protease inactivators reduced bone resorption by 80% in a dose-dependent manner at sub-micromolar concentrations. No reduction of bone resorption was observed at those low concentrations using a potent Cathepsin L, S, B-specific inhibitor. That the inhibition of bone resorption can be attributed to Cathepsin K-liKe protease inhibition was corroborated by the selective inhibition of the osteoclastic Z-Gly-Pro-Arg-MbetaNA hydrolyzing activity by the Cathepsin K, L, S, B-inhibitor, but not by the Cathepsin L, B, and S inhibitor. Z-Gly-Pro-Arg-MbetaNA is efficiently hydrolyzed by Cathepsin K but only poorly by Cathepsins L, S, and B. On the contrary, the intracellular hydrolysis of the Cathepsin B-specific substrate, Z-Arg-Arg-MbetaNA, was prevented by both types of inhibitors. The identification of Cathepsin K in resorption pits and the inhibition of bone resorption and intracellular Cathepsin K activity by selective vinyl sulfone inhibitors indicate the critical role of the protease in osteoclastic bone resorption.
Fabien Lecaille - One of the best experts on this subject based on the ideXlab platform.
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Cathepsin K inhibitors for osteoporosis and potential off target effects
Expert Opinion on Investigational Drugs, 2009Co-Authors: Dieter Brömme, Fabien LecailleAbstract:Cathepsin K is a highly potent collagenase and the predominant papain-liKe cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable Cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of Cathepsin K research and discuss the current development of Cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-ta...
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Cathepsin K inhibitors for osteoporosis and potential off-target effects
Expert Opinion on Investigational Drugs, 2009Co-Authors: Dieter Brömme, Fabien LecailleAbstract:Cathepsin K is a highly potent collagenase and the predominant papain-liKe cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable Cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of Cathepsin K research and discuss the current development of Cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-target effects of Cathepsin K inhibition and alternative applications of Cathepsin K inhibitors in arthritis, atherosclerosis, blood pressure regulation, obesity and cancer.
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biochemical properties and regulation of Cathepsin K activity
Biochimie, 2008Co-Authors: Fabien Lecaille, Dieter Brömme, Gilles LalmanachAbstract:Cysteine Cathepsins (11 in humans) are mostly located in the acidic compartments of cells. They have been Known for decades to be involved in intracellular protein degradation as houseKeeping proteases. However, the discovery of new Cathepsins, including Cathepsins K, V and F, has provided strong evidence that they also participate in specific biological events. This review focuses on the current Knowledge of Cathepsin K, the major bone cysteine protease, which is a drug target of clinical interest. Nevertheless, we will not discuss recent developments in Cathepsin K inhibitor design since they have been extensively detailed elsewhere. We will cover features of Cathepsin K structure, cellular and tissue distribution, substrate specificity, and regulation (pH, propeptide, glycosaminoglycans, oxidants), and its putative roles in physiological or pathophysiological processes. Finally, we will review the Kinetic data of its inhibition by natural endogenous inhibitors (stefin B, cystatin C, H- and L-Kininogens).
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Modulation of hypotensive effects of Kinins by Cathepsin K.
Archives of Biochemistry and Biophysics, 2006Co-Authors: Fabien Lecaille, Dieter Brömme, Christophe Vandier, Emmanuel Godat, Virginie Hervé-grépinet, Gilles LalmanachAbstract:Abstract Kinins are pro-inflammatory peptides, which participate in the maintenance of cardiovascular homeostasis, and play a Key role in numerous diseases, including lung fibrosis and hypertension. Evidence has been provided recently for the presence of alternative mechanisms of bradyKinin generation and/or degradation. Here we showed that Cathepsin K may act as a potent Kinin-degrading enzyme in bloodstream. Contrary to Cathepsin L, Cathepsin K attenuates KalliKrein-induced decrease of rat blood pressure, and reduces the hypotensive effect of bradyKinin in a dose-dependant manner. Moreover, we identified, by engineering the S2 subsite of both recombinant enzymes, two critical residues involved respectively in the Kininase activity of Cathepsin K, i.e. Tyr67/Leu205, versus Kininogenase activity of Cathepsin L, i.e. Leu67/Ala205. In conclusion, according to its ability to modulate hypotensive effects of Kinins, we propose that Cathepsin K is a Kininase of biological relevance, in complement of well-documented neutral endopeptidase or angiotensin-converting enzyme.
J A Gallagher - One of the best experts on this subject based on the ideXlab platform.
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the osteoclast associated protease Cathepsin K is expressed in human breast carcinoma
Cancer Research, 1997Co-Authors: Amanda Littlewoodevans, Tetsuya Inaoka, Toshio Kokubo, Graeme Bilbe, W B Bowler, David Farley, Brenda Wlodarski, John Sloane, Dean B Evans, J A GallagherAbstract:Human Cathepsin K is a novel cysteine protease previously reported to be restricted in its expression to osteoclasts. Immunolocalization of Cathepsin K in breast tumor bone metastases revealed that the invading breast cancer cells expressed this protease, albeit at a lower intensity than in osteoclasts. In situ hybridization and immunolocalization studies were subsequently conducted to demonstrate Cathepsin K mRNA and protein expression in samples of primary breast carcinoma. Expression of Cathepsin K mRNA was confirmed by reverse transcription PCR and Southern analysis in a number of human breast cancer cell lines and in primary human breast tumors and their metastases. As this protease is Known to degrade extracellular matrix, including bone matrix proteins, it is possible that Cathepsin K may contribute to the invasive potential of breast cancer cells, including those that metastasize to bone. Thus, Cathepsin K may be a potential target leading to the design of novel drugs for cancer therapy.
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localization of Cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry
Bone, 1997Co-Authors: Amanda Littlewoodevans, Osamu Ishibashi, Tetsuya Inaoka, Toshio Kokubo, Brenda Wlodarski, J A Gallagher, Graeme BilbeAbstract:Abstract We have recently cloned Cathepsin K from a human bone cDNA library. Since Cathepsins are proposed to be involved in the degradation of mineralized bone matrix, we have investigated, by in situ hybridization and immunocytochemistry, the expression of the Cathepsin K mRNA transcripts and protein in sections of bone and giant cell tumor to determine which cells express this enzyme. Within all tissues studied, Cathepsin K was highly expressed in osteoclasts. Futhermore, the expression of Cathepsin K mRNA in giant cell tumor tissue appeared to be confined to the periphery of the osteoclast indicating a compartmentalization of the mRNA. Immunohistochemistry confirmed the specific localization of Cathepsin K to the osteoclast. In actively resorbing osteoclasts, the immunostaining was localized at the ruffled border, whereas in osteoclasts in sections of giant cell tumor, staining was observed in lysosomal vacuoles, which in some cases were seen to fuse with the cell membrane. Other cells within the bone, such as osteoblasts and osteocytes, did not express either the Cathepsin K transcript or protein. However, there were very low levels of Cathepsin K detected in a population of mononuclear cells, possibly representing osteoclast progenitor cells, within the marrow/stromal layer. The specific localization of Cathepsin K within osteoclasts would therefore indicate the potential role of this enzyme in the bone resorptive process.