title: CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways.
abstract: The osteoclast is an integral cell of bone resorption. Since osteolytic disorders hinge on the function and dysfunction of the osteoclast, understanding osteoclast biology is fundamental to designing new therapies that curb osteolytic disorders. The identification and study of lysosomal proteases, such as cathepsins, have shed light on mechanisms of bone resorption. For example, Cathepsin K has already been identified as a collagen degradation protease produced by mature osteoclasts with high activity in the acidic osteoclast resorption pits. Delving into the mechanisms of cathepsins and other osteoclast related compounds provides new targets to explore in osteoclast biology. Through our anti-osteoclastogenic compound screening experiments we encountered a modified version of the Cathepsin B inhibitor CA-074: the cell membrane-permeable CA-074Me (L-3-trans-(Propylcarbamoyl) oxirane-2-carbonyl]-L-isoleucyl-L-proline Methyl Ester). Here we confirm that CA-074Me inhibits osteoclastogenesis in vivo and in vitro in a dose-dependent manner. However, Cathepsin B knockout mice exhibited unaltered osteoclastogenesis, suggesting a more complicated mechanism of action than Cathepsin B inhibition. We found that CA-074Me exerts its osteoclastogenic effect within 24 h of osteoclastogenesis stimulation by suppression of c-FOS and NFATc1 pathways.
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Neel
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Saqib
authors.initials: S
authors.lastname: Nizami
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Lee
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.|Department of Anesthesiology, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Maya
authors.initials: M
authors.lastname: Mikami
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Anny
authors.initials: A
authors.lastname: Hsu
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hickernell
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Chandhanarat
authors.initials: C
authors.lastname: Chandhanayingyong
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Shim
authors.initials: S
authors.lastname: Rho
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.|Department of Medicine, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Jocelyn T
authors.initials: JT
authors.lastname: Compton
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Jon-Michael
authors.initials: JM
authors.lastname: Caldwell
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.|Department of Medicine, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Kaiser
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Hanying
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Heon Goo
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Charla R
authors.initials: CR
authors.lastname: Fischer
authors.affiliation: Department of Orthopaedic Surgery, Columbia University, 650 West 168th Street BB14-1412, NY, 10032, New York.
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000172:deficiency; D004151:Dipeptides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors*; D053245:RANK Ligand
chemical_list: C400541:CA 074 methyl ester; D004151:Dipeptides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D002401:Cathepsin B
keywords: CA-074Me; NFATc1; Osteoclasts; RANKL; c-Fos