Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 35, No. 2, 284-295 (2007)
DOI: 10.1080/01926230701198469

Articles

Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats

Kendall Frazier, Roberta Thomas, Marshall Scicchitano, Rosanna Mirabile, Rogely Boyce, Dawn Zimmerman, Eugene Grygielko, James Nold, Anne-Charlotte DeGouville, Stephane Huet, Nicholas Laping and Francoise Gellibert

GlaxoSmithKline—Safety Assessment, King of Prussia, PA 19406, USA

Correspondence: Address correspondence to: Kendall Frazier, GlaxoSmithKline-Safety Assessment, 709 Swedeland Road, UE0376 PO Box 1539 King of Prussia, PA 19406, USA; e-mail:kendall.s.frazier{at}gsk.com

TGF-|β|, and its type 1 (ALK5) receptor, are critical to the pathogenesis of fibrosis. In toxicologic studies of 4 or more days in 10-week-old Sprague–Dawley rats, using an ALK5 inhibitor (GW788388), expansion of hypertrophic and proliferation zones of femoral physes were noted. Subphyseal hyperostosis, chondrocyte hypertrophy/hyperplasia, and increased matrix were present. Physeal zones were laser microdissected from ALK5 inhibitor-treated and control rats sacrificed after 3 days of treatment. Transcripts for TGF-|β|1, TGF-|β|2, ALK5, IHH, VEGF, BMP-7, IGF-1, bFGF, and PTHrP were amplified by real-time PCR. IGF and IHH increased in all physis zones with treatment, but were most prominent in prehypertrophic zones. TGF-|β|2, bFGF and BMP7 expression increased in proliferative, pre- and hypertrophic zones. PTHrP expression was elevated in proliferative zones but decreased in hypertrophic zones. VEGF expression was increased after treatment in pre- and hypertrophic zones. ALK5 expression was elevated in prehypertrophic zones. Zymography demonstrated gelatinolytic activity was reduced after treatment. Apoptotic markers (TUNEL and caspase-3) were decreased in hypertrophic zones. Proliferation assessed by Topoisomerase II and Ki67 was increased in multiple zones. Movat stains demonstrated that proteoglycan deposition was altered. Physeal changes occurred at doses well above those resulting in fibrosis. Interactions of factors is important in producing the physeal dysplasia phenotype.

Key Words: Preclinical safety-assessment/risk management • molecular pathology • rat pathology • musculoskeletal system • microdissection • mechanisms of toxicity


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