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Calcified Tissue International Feb 2018Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve... (Review)
Review
Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs initially thought to target only osteoclasts are now known to have a dual action (activating osteoblasts and inhibiting osteoclasts, e.g. proteasome inhibitors). This review will focus on the evolution of bone-targeted therapies for the treatment of cancer-induced bone disease, summarizing preclinical and clinical findings obtained with anti-resorptive and bone anabolic therapies.
Topics: Androgen Antagonists; Bone Neoplasms; Bortezomib; Cathepsin K; Denosumab; Diphosphonates; Humans; Integrins; Molecular Targeted Therapy; Proteasome Inhibitors; Proto-Oncogene Proteins pp60(c-src); Radiopharmaceuticals; TOR Serine-Threonine Kinases
PubMed: 29079995
DOI: 10.1007/s00223-017-0353-5 -
Expert Opinion on Investigational Drugs May 2009Cathepsin K is a highly potent collagenase and the predominant papain-like cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have... (Review)
Review
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.
Topics: Animals; Cathepsin K; Cysteine Proteinase Inhibitors; Humans; Osteoporosis
PubMed: 19388876
DOI: 10.1517/13543780902832661 -
Biochimica Et Biophysica Acta.... Nov 2017The proteolytic processing of collagen (collagenolysis) is critical in development and homeostasis, but also contributes to numerous pathologies. Mammalian interstitial... (Review)
Review
The proteolytic processing of collagen (collagenolysis) is critical in development and homeostasis, but also contributes to numerous pathologies. Mammalian interstitial collagenolytic enzymes include members of the matrix metalloproteinase (MMP) family and cathepsin K. While MMPs have long been recognized for their ability to catalyze the hydrolysis of collagen, the roles of individual MMPs in physiological and pathological collagenolysis are less defined. The use of knockout and mutant animal models, which reflect human diseases, has revealed distinct collagenolytic roles for MT1-MMP and MMP-13. A better understanding of temporal and spatial collagen processing, along with the knowledge of the specific MMP involved, will ultimately lead to more effective treatments for cancer, arthritis, cardiovascular conditions, and infectious diseases. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
Topics: Animals; Arthritis; Cathepsin K; Humans; Infections; Matrix Metalloproteinase 13; Matrix Metalloproteinase 14; Neoplasm Proteins; Neoplasms
PubMed: 28456643
DOI: 10.1016/j.bbamcr.2017.04.015 -
Journal of Enzyme Inhibition and... Dec 2018Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a... (Review)
Review
Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors. These inhibitors are derived from synthetic compounds or natural products, some of which have passed preclinical studies and are presently in clinical trials at different stages of advancement. In this review, we briefly summarised the historic development of Cat K inhibitors and discussed the relationship between structures of inhibitors and active sites in Cat K for the purpose of guiding future development of inhibitors.
Topics: Animals; Bone Resorption; Cathepsin K; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 29723068
DOI: 10.1080/14756366.2018.1465417 -
British Journal of Clinical Pharmacology Jun 2019Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal... (Review)
Review
Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.
Topics: Animals; Biphenyl Compounds; Bone Density Conservation Agents; Bone Remodeling; Bone and Bones; Cathepsin K; Cysteine Proteinase Inhibitors; Female; Humans; Male; Osteoporosis; Signal Transduction; Translational Research, Biomedical; Treatment Outcome
PubMed: 30663085
DOI: 10.1111/bcp.13869 -
Hypertension (Dallas, Tex. : 1979) Aug 2022Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various...
BACKGROUND
Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress.
METHODS
Male 7-week-old WT (wild type; CatK) and CatK-deficient (CatK) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation.
RESULTS
Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22, gp91, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy-related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK's involvement in PPAR-γ/caspase-8-mediated cell apoptosis in response to superoxide and stressed serum.
CONCLUSIONS
These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.
Topics: Animals; Caspase 8; Cathepsin K; Humans; Hypertension; Kidney; Kidney Diseases; Male; Mice; Nephrectomy; Peroxisome Proliferator-Activated Receptors; Potassium Deficiency; Stress, Physiological
PubMed: 35726642
DOI: 10.1161/HYPERTENSIONAHA.122.19137 -
Journal of Cancer Research and Clinical... Aug 2019The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases,...
BACKGROUND
The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone.
METHODS
CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses.
RESULTS
We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA).
CONCLUSION
The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.
Topics: Adenocarcinoma; Animals; Bone Neoplasms; Cathepsin K; Cell Proliferation; Cells, Cultured; Humans; Male; Mice; Mice, SCID; Molecular Targeted Therapy; PC-3 Cells; Prostatic Neoplasms; Protease Inhibitors; RNA, Small Interfering; Xenograft Model Antitumor Assays
PubMed: 31172267
DOI: 10.1007/s00432-019-02950-y -
JCI Insight Oct 2020Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further...
Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab-deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β-related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.
Topics: Animals; Cathepsin K; Disease Models, Animal; Enzyme Activation; Genetic Predisposition to Disease; Heart; Heart Defects, Congenital; Heart Valves; Humans; Lysosomal Storage Diseases; Mucolipidoses; Mutation; Transferases (Other Substituted Phosphate Groups); Transforming Growth Factor beta; Zebrafish
PubMed: 33055423
DOI: 10.1172/jci.insight.133019 -
Cell Death & Disease Sep 2022A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the...
A common stage of advanced prostate cancer is castration-resistant prostate cancer (CRPC), greater understanding of which is required in order to address and solve the clinically difficult challenge. Cathepsin K (CTSK) is a cysteine protease that usually has a strong activity of degrading extracellular matrix and is related to osteoclast-mediated bone destruction. However, the mechanism of CTSK-regulation in CRPC is still unclear to us. The current study aimed to analyze the expression of differentially expressed genes (DEGs) in patient samples (from localized PC and CRPC). Interestingly, we found that CTSK to be significantly up-regulated in CRPC. Through further signal pathway enrichment analysis, we found that the IL-17 signaling pathway to be highly correlated with CTSK. The oncogenic functions of CTSK and IL-17 in CRPC were proven by a series of in vivo and in vitro experiments. Possible downstream molecules of CTSK were investigated, which could serve as control elements to regulate the expression of EMT, thereby facilitating the metastasis and excessive proliferation of PC cells. Expression of CTSK was related to high concentration of M2 tumor-associated macrophages (TAMs) M2 in CRPC. A CTSK-mediated feedback circuit between TAMs and CRPC tissues was indicated in the process of transfer, proving the possibility of CTSK could be use as an available therapeutic target for CRPC.
Topics: Cathepsin K; Cell Line, Tumor; Humans; Interleukin-17; Macrophages; Male; Prostatic Neoplasms, Castration-Resistant
PubMed: 36138018
DOI: 10.1038/s41419-022-05215-8 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Sep 2022To investigate the effects of Cathepsin K(CatK) on spatial learning and memory in rat hippocampus and its mechanisms.
OBJECTIVE
To investigate the effects of Cathepsin K(CatK) on spatial learning and memory in rat hippocampus and its mechanisms.
METHODS
Twenty male SD rats were randomly divided into Control group and CatK inhibitor group(CatKⅡ group), which were microinjected with Cathepsin K specific inhibitor(0.5 μg/μl) and artificial cerebrospinal fluid in hippocampal DG area respectively with 5 days. The cultured hippocampal neuron cells were divided into control group (CON group), negative control group(NC group), siRNA interference group(siCatK group). Three re-wells were set for each group, and samples were collected 18~20 h after siRNA transfection. Morris water maze was used to evaluate spatial learning and memory function of rats. Meanwhile, dynamic changes of glutamate(Glu) content in extracellular fluid of DG region during learning and memory were observed by microdialysis and high performance liquid chromatography in conscious rats. Western blot was used to detect CatK-mediated Notch1 activation and other signal molecules.
RESULTS
Animal experiments showed that compared with the control group, the spatial learning and memory ability were decreased significantly in CatKII group, and the hippocampus protein expressions of c-Notch1, p-Akt, p-CREB and BDNF were also decreased significantly(<0.05); the levels of Glu in DG area of control group and CatK II group were increased significantly with Morris water maze training days, but the increase of CatK II group was significantly weaker than that of control group(< 0.05). The results of cell experiment showed that the expressions of CatK, c-Notch1, p-CREB and BDNF in siCatK group were significantly lower than other groups (<0.05).
CONCLUSION
CatK can affect the spatial learning and memory function of rats by activating Notch1 and its memory related signal protein in hippocampus.
Topics: Animals; Rats; Rats, Sprague-Dawley; Male; Spatial Learning; Memory; Cathepsin K; Hippocampus; Receptor, Notch1
PubMed: 37088743
DOI: 10.12047/j.cjap.6311.2022.077