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Effects of Long‐Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate
Author(s) -
Muise Eric S,
Podtelezhnikov Alexei A,
Pickarski Maureen,
Loboda Andrey,
Tan Yejun,
Hu Guanghui,
Thomspon John R,
Duong Le T
Publication year - 2016
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2752
Subject(s) - cathepsin k , bone remodeling , bone resorption , osteoclast , n terminal telopeptide , ovariectomized rat , endocrinology , medicine , bisphosphonate , runx2 , tartrate resistant acid phosphatase , bone mineral , cathepsin , bone density , osteoporosis , biology , osteocalcin , chemistry , gene expression , alkaline phosphatase , estrogen , gene , receptor , biochemistry , enzyme
ABSTRACT Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)‐monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets ( p < 0.001, three‐group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone‐related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption–related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation–related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C‐terminal cross‐linked telopeptide (1‐CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates. © 2016 American Society for Bone and Mineral Research.