Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

Gao

J of Cellular Biochemistry

et al. 2018

Osteoporosis is a common orthopedic disease which is associated with hyper-activated osteoclastogenesis. Daphnetin is a natural coumarin derivative isolated from Genus Daphne, which possesses antiarthritis effect. However, the role of daphnetin in osteoclastogenesis has not been illustrated. This study aimed to investigate the effects of daphnetin on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in vitro. Our results showed that the osteoclast formation was significantly suppressed by daphnetin treatment in bone marrow-derived macrophages (BMMs), which was illustrated by reduced number of tartrate-resistant acid phosphatase positive multinucleated osteoclasts and decreased expression levels of tumor necrosis factor receptor-associated factors (TRAF6), c-Fos, nuclear factor of activated T cells c1, and cathepsin K. RANKL caused significant induction effects in reactive oxygen species (ROS) generation and nicotinamide adenine dinucleotide phosphate oxidase activity, whereas the induction was dramatically reduced after pretreatment with daphnetin. In addition, daphnetin prevented the RANKL-induced activation of NF-κB and Akt/GSK-3β pathways in BMMs. These findings indicated that daphnetin exhibited an inhibitory effect on RANKL-induced osteoclastogenesis in vitro. The effect of daphnetin might be mediated by inhibiting ROS signal transduction, as well as preventing the activation of NF-κB and Akt/GSK-3β signaling pathways. These findings indicated that daphnetin might be considered as a new therapeutic approach for the osteoporosis treatment.

Section: Discussionmentioning

confidence: 99%

Daphnetin inhibits RANKL‐induced osteoclastogenesis in vitro

Gao

J of Cellular Biochemistry

et al. 2018

“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

Zeitschrift Für Kristallographie - Crystalline Materials

“…Thus, in order to design a powerful and specific Cathepsin inhibitor, it is of fundamental importance to have detailed knowledge of the features of each sub-site of each Cathepsin [37][38][39]. In addition, it is worth highlighting that this class of enzyme is related to several pathological processes such as osteoporosis (Cathepsin K) [40,41], neurodegenerative disease (Cathepsin D) [42] and metastasis in several types of cancer (Cathepsins B, K, L and S) [43][44][45]. Hence, Cathepsins are promising targets for the treatment of such disorders [46].…”

Section: Decane (1) (3e)-2-chloro-3-(chloromethylidene)-2-(4-methoxymentioning

confidence: 99%

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

Caracelli

Maganhi

Cardoso

et al. 2017

Abstract. The molecular structures of the halotelluroxetanes pMeOC6H4Te(X)[C(=C(H)Xꞌ)C(CH2)nO], X = Xꞌ = Cl and n = 6 (1) and X = Cl, Xꞌ = Br and n = 5 (4), show similar binuclear aggregates sustained by { … Te-O}2 cores comprising covalent Te-O and secondary Te⋯O interactions. The resulting C2ClO2(lone-pair) sets define pseudo-octahedral geometries. In each structure, C-X⋯(arene) interactions lead to supramolecular layers. Literature studies have shown these and related compounds (i.e. 2: X = Xꞌ = Cl and n = 5; 3: X = Xꞌ = Br and n = 5) to inhibit Cathepsins B, K, L and S to varying extents. Molecular docking calculations have been conducted on ligands (i.e. cations derived by removal of the telluriumbound X atoms) 1ꞌ-3ꞌ (note 3ꞌ = 4ꞌ) enabling correlations between affinity for sub-sites and inhibition. The common feature of all docked complexes was the formation of a Te-S covalent bond with cysteine residues, the relative stability of the ligands with an E-configuration and the formation of a C-O … π interaction with the phenyl ring; for 1ꞌ the Te-S covalent bond was weak, a result correlating with its low inhibition profile. At the next level differences are apparent, especially with respect to the interactions formed by the organic-ligand-bound halides.