scholarly journals Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish

RSC Advances ◽  
2019 ◽  
Vol 9 (15) ◽  
pp. 8600-8607 ◽  
Author(s):  
Si-tu Xue ◽  
Ya-li Wang ◽  
Xiao-wan Han ◽  
Hong Yi ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Bone Density ◽  
Cysteine Protease ◽  
Cathepsin K ◽  
Cathepsin K Inhibitors

Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts.

Erratum to ‘Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts’

Bone ◽  
2021 ◽  
Vol 145 ◽  
pp. 115354
Author(s):  
Karen Fuller ◽  
Kevin M. Lawrence ◽  
Jade L. Ross ◽  
Urszula B. Grabowska ◽  
Masahiro Shiroo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cathepsin K ◽  
Cathepsin K Inhibitors ◽  
Human Osteoclasts

Cathepsin K inhibitors based on 2-amino-1,3,4-oxadiazole derivatives

2021 ◽  
Vol 109 ◽  
pp. 104662
Author(s):  
Talita B. Gontijo ◽  
Patrícia S. Lima ◽  
Marcelo Y. Icimoto ◽  
Raquel Leão Neves ◽  
Érika C. de Alvarenga ◽  
...  
Keyword(s):  
Cathepsin K ◽  
Cathepsin K Inhibitors ◽  
Oxadiazole Derivatives

Solid-phase synthesis of cyclic alkoxyketones, inhibitors of the cysteine protease cathepsin K

2001 ◽  
Vol 11 (2) ◽  
pp. 195-198 ◽  
Author(s):  
Ashley E. Fenwick ◽  
Bénédicte Garnier ◽  
Andrew D. Gribble ◽  
Robert J. Ife ◽  
Anthony D. Rawlings ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Solid Phase Synthesis ◽  
Solid Phase ◽  
Cathepsin K ◽  
Phase Synthesis

scholarly journals The Porcine Reproductive and Respiratory Syndrome Virus nsp2 Cysteine Protease Domain Possesses both trans- and cis-Cleavage Activities

2009 ◽  
Vol 83 (18) ◽  
pp. 9449-9463 ◽  
Author(s):  
Jun Han ◽  
Mark S. Rutherford ◽  
Kay S. Faaberg
Keyword(s):  
Cysteine Protease ◽  
Reverse Genetics ◽  
Nonstructural Protein ◽  
Point Mutations ◽  
Respiratory Syndrome Virus ◽  
Protease Domain ◽  
Nonstructural Protein 2 ◽  
Cleavage Activity ◽  
Cysteine Protease Domain

ABSTRACT The N terminus of the replicase nonstructural protein 2 (nsp2) of porcine reproductive and respiratory syndrome virus (PRRSV) contains a putative cysteine protease domain (PL2). Previously, we demonstrated that deletion of either the PL2 core domain (amino acids [aa] 47 to 180) or the immediate downstream region (aa 181 to 323) is lethal to the virus. In this study, the PL2 domain was found to encode an active enzyme that mediates efficient processing of nsp2-3 in CHO cells. The PL2 protease possessed both trans- and cis-cleavage activities, which were distinguished by individual point mutations in the protease domain. The minimal size required to maintain these two enzymatic activities included nsp2 aa 47 to 240 (Tyr47 to Cys240) and aa 47 to 323 (Tyr47 to Leu323), respectively. Introduction of targeted amino acid mutations in the protease domain confirmed the importance of the putative Cys55- His124 catalytic motif for nsp2/3 proteolysis in vitro, as were three additional conserved cysteine residues (Cys111, Cys142, and Cys147). The conserved aspartic acids (e.g., Asp89) were essential for the PL2 protease trans-cleavage activity. Reverse genetics revealed that the PL2 trans-cleavage activity played an important role in the PRRSV replication cycle in that mutations that impaired the PL2 protease trans function, but not the cis activity, were detrimental to viral viability. Lastly, the potential nsp2/3 cleavage site was probed. Mutations with the largest impact on in vitro cleavage were at or near the G1196|G1197 dipeptide.

Cells in regenerating deer antler cartilage provide a microenvironment that supports osteoclast differentiation

2001 ◽  
Vol 204 (3) ◽  
pp. 443-455
Author(s):  
C. Faucheux ◽  
S. Nesbitt ◽  
M. Horton ◽  
J. Price
Keyword(s):  
Type I Collagen ◽  
Mononuclear Cells ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Collagen Matrix ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Deer Antler

Deer antlers are a rare example of mammalian epimorphic regeneration. Each year, the antlers re-grow by a modified endochondral ossification process that involves extensive remodelling of cartilage by osteoclasts. This study identified regenerating antler cartilage as a site of osteoclastogenesis in vivo. An in vitro model was then developed to study antler osteoclast differentiation. Cultured as a high-density micromass, cells from non-mineralised cartilage supported the differentiation of large numbers of osteoclast-like multinucleated cells (MNCs) in the absence of factors normally required for osteoclastogenesis. After 48 h of culture, tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells (osteoclast precursors) were visible, and by day 14 a large number of TRAP-positive MNCs had formed (783+/−200 per well, mean +/− s.e.m., N=4). Reverse transcriptase/polymerase chain reaction (RT-PCR) showed that receptor activator of NF κ B ligand (RANKL) and macrophage colony stimulating factor (M-CSF) mRNAs were expressed in micromass cultures. Antler MNCs have the phenotype of osteoclasts from mammalian bone; they expressed TRAP, vitronectin and calcitonin receptors and, when cultured on dentine, formed F-actin rings and large resorption pits. When cultured on glass, antler MNCs appeared to digest the matrix of the micromass and endocytose type I collagen. Matrix metalloproteinase-9 (MMP-9) may play a role in the resorption of this non-mineralised matrix since it is highly expressed in 100 % of MNCs. In contrast, cathepsin K, another enzyme expressed in osteoclasts from bone, is only highly expressed in resorbing MNCs cultured on dentine. This study identifies the deer antler as a valuable model that can be used to study the differentiation and function of osteoclasts in adult regenerating mineralised tissues.

A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys

Bone ◽  
2007 ◽  
Vol 40 (1) ◽  
pp. 122-131 ◽  
Author(s):  
S. Kumar ◽  
L. Dare ◽  
J.A. Vasko-Moser ◽  
I.E. James ◽  
S.M. Blake ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Potent Inhibitor ◽  
Cathepsin K
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