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Cathepsin k inhibitors

Dong Ryun Gu, Joon No Lee, Gi-Su Oh, Hyung Jin Kim, Min Seuk Kim, Seoung Hoon Lee
β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis...
November 29, 2016: Biochemical and Biophysical Research Communications
H Hussein, J Dulin, L Smanik, W T Drost, D Russell, M Wellman, A Bertone
Our investigations evaluated the effect of VEL-0230, a highly specific irreversible inhibitor of cathepsin K (CatK). The objectives of our study were to determine whether repeated dosing of a CatK inhibitor (CatKI) produced a desired inhibition of the bone resorption biomarker (CTX-1), and document the effect of repeated dosing on bone homeostasis, structure, and dynamics of bone resorption and formation in horses. Twelve young exercising horses were randomized in a prospective, controlled clinical trial and received 4 weekly doses of a CatKI or vehicle...
November 24, 2016: Journal of Veterinary Pharmacology and Therapeutics
Hongyan Liu, Guoqi Wang, Weijun Gu, Yiming Mu
Pituitary adenomas with sphenoid sinus or clivus invasion are not uncommon, but the pathogenesis responsible for this phenomenon remains unclear. Cathepsin K, expressed predominantly in osteoclasts, can degrade type I collagen and plays an essential role in bone resorption. Recent studies reported the expression of Cathepsin K in various malignant tumors, such as bone, breast, lung and prostate cancers, and its expression is further increased in bone metastasis or invasive subpopulations. In addition, cathepsin K inhibitors (CatKi) were demonstrated to effectively prevent or reduce osteolytic lesions in breast cancers with bone metastasis...
December 2016: Medical Hypotheses
Steven L Teitelbaum
Anti-resorptive therapy is the principal means of treating osteoporotic disorders. The two families of presently available anti-resorptive drugs, namely bisphosphonates and denosumab, dampen activity of osteoclasts by reducing their number. In consequence, these agents also arrest bone remodelling eventuating suppressed formation as well as resorption. Evidence exists that osteoclasts recruit osteoblasts to sites of bone remodelling by mobilizing chemotactic proteins from matrix and direct secretion of such proteins that attract osteoblast precursors...
December 2016: Rheumatology
Jie Zhang, Haixia Xu, Zhongyu Han, Ping Chen, Qiang Yu, Yutian Lei, Zongze Li, Ming Zhao, Jing Tian
Pulsed electromagnetic field (PEMF) has been reported to improve bone healing in osteoporosis patients. However, the precise mechanism has remained largely unknown. This study aimed to investigate the effects of PEMF on nuclear factor κB ligand (RANKL)-dependent osteoclastic differentiation and the Ca(2+)-calcineurin-NFATc1 signaling pathway in RAW264.7 cells in vitro. Treating RAW264.7 cells with RANKL for 4 days induced osteoclastic differentiation in vitro, and the formation of multinucleated osteoclasts, bone resorption-pit formation, tartrate-resistant acid phosphatase (TRAP) activity and the protein levels of cathepsin K, TRAP, Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and matrix metalloproteinase 9 (MMP-9) were significantly decreased...
November 14, 2016: Biochemical and Biophysical Research Communications
Matthew Huisman, Jessica K White, Veronica G Lewalski, Izabela Podgorski, Claudia Turro, Jeremy J Kodanko
Photochemical control over irreversible inhibition was shown using Ru(ii)-caged inhibitors of cathepsin L. Levels of control were dependent on where the Ru(ii) complex was attached to the organic inhibitor, reaching >10 : 1 with optimal placement. A new strategy for photoreleasing Ru(ii) fragments from inhibitor-enzyme conjugates is also reported.
October 18, 2016: Chemical Communications: Chem Comm
Youshan Li, Huawei Liu, Rui Zhu, Qingyou Xia, Ping Zhao
Previous studies have indicated that most trypsin inhibitor-like cysteine-rich domain (TIL)-type protease inhibitors, which contain a single TIL domain with ten conserved cysteines, inhibit cathepsin, trypsin, chymotrypsin, or elastase. Our recent findings suggest that Cys(2nd) and Cys(6th) were lost from the TIL domain of the fungal-resistance factors in Bombyx mori, BmSPI38 and BmSPI39, which inhibit microbial proteases and the germination of Beauveria bassiana conidia. To reveal the significance of these two missing cysteines in relation to the structure and function of TIL-type protease inhibitors in B...
December 2016: Peptides
Zhen Tan, Jianwen Cheng, Qian Liu, Lin Zhou, Jacob Kenny, Tao Wang, Xixi Lin, Jinbo Yuan, Julian M W Quinn, Jennifer Tickner, Guoju Hong, An Qin, Jinmin Zhao, Jiake Xu
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K...
September 21, 2016: Molecular and Cellular Endocrinology
Le T Duong, Randy Crawford, Kevin Scott, Christopher T Winkelmann, Gouxin Wu, Pete Szczerba, Michael A Gentile
Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7...
September 15, 2016: Bone
Donna Lee M Dinnes, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mi-Jurng Kim, Liming Hou, Wendy Jessup, Kerry-Anne Rye, Morten Thaysen-Andersen, Stuart J Cordwell, Leonard Kritharides
Apolipoprotein A-I (apoA-I) is the major component of HDL and central to the ability of HDL to stimulate ATP-binding cassette transporter A1 (ABCA1)-dependent, antiatherogenic export of cholesterol from macrophage foam cells, a key player in the pathology of atherosclerosis. Cell-mediated modifications of apoA-I, such as chlorination, nitration, oxidation, and proteolysis, can impair its antiatherogenic function, although it is unknown whether macrophages themselves contribute to such modifications. To investigate this, human monocyte-derived macrophages (HMDMs) were incubated with human apoA-I under conditions used to induce cholesterol export...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rui Xing, Yingjian Zhang, Changhong Li, Lin Sun, Lin Yang, Jinxia Zhao, Xiangyuan Liu
Cytokines play a key role in the bone destruction of rheumatoid arthritis (RA). Interleukin-21 (IL-21) promotes osteoclastogenesis in RA in a receptor activator of nuclear factor-κB ligand (RANKL)-dependent way. Whether IL-21 is capable of promoting osteoclastogenesis directly in the absence of RANKL remains unknown. In the present study, we examined the osteoclastogenic activity of IL-21 in RAW264.7 cells in the absence of RANKL. We found that IL-21 enhanced osteoclastogenesis and this was demonstrated by increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive stained, multinucleated cells compared with the negative control...
October 2016: International Journal of Molecular Medicine
Catera L Wilder, Charlene Walton, Valencia Watson, Fermin A A Stewart, Jade Johnson, Shelly R Peyton, Christine K Payne, Valerie Odero-Marah, Manu O Platt
Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors...
October 2016: International Journal of Biochemistry & Cell Biology
Song-Yan Hu, Xiao-Dong Jin, Hao Zhang, Jun Chen, Guo-Zhu Yang, Xiao-Dong Wang, Lu Tang, Xing-Yan Lu, Li Lu, Qing-Nan Li
OBJECTIVE: To explore the role of epithelial sodium channel (ENaC) in regulating the functional activity of osteoclasts. METHODS: Multinucleated osteoclasts were obtained by inducing the differentiation of rat bone marrow cells with macrophage colony-stimulating factor (M-CSF) and RANKL. The osteoclasts were exposed to different concentrations of the ENaC inhibitor amiloride, and the expression of ENaC on osteoclasts was examined using immunofluorescence technique...
August 20, 2016: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Anna Cline-Smith, Jesse Gibbs, Elena Shashkova, Zachary S Buchwald, Deborah V Novack, Rajeev Aurora
A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3(+)CD25(+) regulatory CD8(+) T cells (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG...
August 18, 2016: JCI Insight
Christopher K Y Chan, Alice Mason, Cyrus Cooper, Elaine Dennison
INTRODUCTION: Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population, its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualize the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies-in the form of combinations and altered durations of existing treatments, as well as newer drug therapies...
September 2016: British Medical Bulletin
Xing Xu, Xueyu Qi, Yufei Yan, Jin Qi, Niandong Qian, Lei Guo, Changwei Li, Fei Wang, Ping Huang, Hanbing Zhou, Min Jiang, Chunhao Yang, Lianfu Deng
Approaches of targeting excessive activation and differentiation of osteoclasts were considered as an effective treatment option for osteoporosis or osteopenia. In the present work, a series of rhein derivatives were synthesized and employed for their cytotoxicity screening against bone marrow-derived macrophages cells (BMMs) and their inhibition effects on osteoclasts activation and differentiation in vitro using an MTT assay and a TRAP activity assay respectively. Two rhein derivatives d6 and d11 inhibited BMMs activation and differentiation with 98% and 85% inhibitory activity respectively, without showing any cytotoxicity on BMMs...
November 10, 2016: European Journal of Medicinal Chemistry
Michael Regn, Bernhard Laggerbauer, Claudia Jentzsch, Deepak Ramanujam, Andrea Ahles, Sonja Sichler, Julia Calzada-Wack, Rory Koenen, Attila Braun, Bernhard Nieswandt, Stefan Engelhardt
A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol-(GPI) membrane anchor...
August 15, 2016: Journal of Molecular and Cellular Cardiology
Minsuk Kwon, Jin-Man Kim, Kyunghee Lee, So-Young Park, Hyun-Sook Lim, Taesoo Kim, Daewon Jeong
Osteoclast progenitors undergo cell cycle arrest before differentiation into osteoclasts, induced by exposure to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The role of such cell cycle arrest in osteoclast differentiation has remained unclear, however. We here examined the effect of synchronized cell cycle arrest on osteoclast formation. Osteoclast progenitors deprived of M-CSF in culture adopted a uniform morphology and exhibited cell cycle arrest at the G₀-G₁ phase in association with both down-regulation of cyclins A and D1 as well as up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1)...
2016: International Journal of Molecular Sciences
Adeleke H Aguda, Vincent Lavallee, Ping Cheng, Tina M Bott, Labros G Meimetis, Simon Law, Nham T Nguyen, David E Williams, Jadwiga Kaleta, Ivan Villanueva, Julian Davies, Raymond J Andersen, Gary D Brayer, Dieter Brömme
Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach...
August 26, 2016: Journal of Natural Products
Tsuyoshi Sato, Yuichiro Enoki, Yasushi Sakamoto, Kazuhiro Yokota, Masahiko Okubo, Masahito Matsumoto, Naoki Hayashi, Michihiko Usui, Shoichiro Kokabu, Toshihide Mimura, Yoshihiko Nakazato, Nobuo Araki, Toru Fukuda, Yasushi Okazaki, Tatsuo Suda, Shu Takeda, Tetsuya Yoda
OBJECTIVE: Donepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro...
September 2015: Heliyon
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