UNASSIGNED: Inhibition of @entity14539 with @entity14539 antibody (Scl-Ab) has been shown to stimulate bone formation, decrease bone resorption, and increase bone mass in both animals and @entity1 . To obtain insight into the temporal cellular and transcriptional changes in the osteoblast (OB) lineage associated with long-term Scl-Ab treatment, stereological and transcriptional analyses of the OB lineage were performed on lumbar vertebrae from aged ovariectomized @entity35 . Animals were administered Scl-Ab 3 or 50mg/kg/wk or vehicle (VEH) for up to 26weeks (d183), followed by a treatment-free period (TFP). At 50mg/kg/wk, bone volume (BV/total volume [TV]) increased through d183 and declined during the TFP. Bone formation rate ( @entity79 [ @entity79 ]) and total OB number increased through d29, then progressively declined, coincident with a decrease in total osteoprogenitor (OP) numbers from d29 through d183. Analysis of differentially expressed genes (DEGs) from microarray analysis of mRNA isolated from laser capture microdissection samples enriched for OB, lining cells, and osteocytes (OCy) revealed modules of genes that correlated with BFR/ @entity79 , BV/TV, and osteoblastic surface (Ob.S)/ @entity79 . Expression change of canonical Wnt target genes was similar in all three cell types at d8, including upregulation of @entity70019 and @entity70020 . At d29, the pattern of Wnt target gene expression changed in the OCy, with @entity70019 returning to VEH level, sustained upregulation of @entity70020 , and upregulation of several other Wnt targets that continued into the TFP. Predicted activation of pathways recognized to integrate with and regulate canonical Wnt signaling were also activated at d29 in the OCy. The most significantly affected pathways represented transcription factor signaling known to inhibit cell cycle progression (notably @entity10740 ) and mitogenesis (notably @entity4569 ). These changes occurred at the time of peak BFR/ @entity79 and continued as BFR/ @entity79 declined during treatment, then trended toward VEH level in the TFP. Concurrent with this transcriptional switch was a reduction in OP numbers, an effect that would ultimately limit bone formation. This study confirms that the initial transcriptional response in response to Scl-Ab is activation of canonical Wnt signaling and the data demonstrate that there is induction of additional regulatory pathways in OCy with long-term treatment. The interactions between Wnt and @entity10740 / @entity4569 signaling may be key in limiting OP populations, thus contributing to self-regulation of bone formation with continued Scl-Ab administration.

Time-dependent cellular and transcriptional changes in the osteoblast lineage associated with sclerostin antibody treatment in ovariectomized XXXX .

@entity1 :: ('9606', 'Species') :: ['humans'] @entity10740 :: ('301300(Tax:10116)', 'Gene') :: ['p53'] @entity70019 :: ('85489(Tax:10116)', 'Gene') :: ['Twist1'] @entity4569 :: ('24577(Tax:10116)', 'Gene') :: ['c-Myc'] @entity70020 :: ('65154(Tax:10116)', 'Gene') :: ['Wisp1'] @entity14539 :: ('50964', 'Gene') :: ['sclerostin'] @entity79 :: ('MESH:D001847', 'Disease') :: ['BS', 'BFR/bone surface'] @entity35 :: ('10116', 'Species') :: ['rats']
@entity35 :: (10116,Species) :: ['rats']
