Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats

Autor: Roberta A. Thomas, Kendall S. Frazier, Stephane Huet, Nicholas J. Laping, Françoise Gellibert, Rogely W. Boyce, Anne-Charlotte DeGouville, James Nold, Rosanna C. Mirabile, Dawn Zimmerman, Marshall S. Scicchitano, Eugene T. Grygielko
Rok vydání: 2007
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
medicine.medical_specialty
Pathology
040301 veterinary sciences
Receptor
Transforming Growth Factor-beta Type I
Chondrocyte hypertrophy
Protein Serine-Threonine Kinases
Biology
Toxicology
Pathology and Forensic Medicine
Rats
Sprague-Dawley
0403 veterinary science
Pathogenesis
03 medical and health sciences
Transforming Growth Factor beta
Fibrosis
Internal medicine
medicine
Animals
Zymography
Growth Plate
Receptor
Molecular Biology
Cell Proliferation
Bone Diseases
Developmental
TUNEL assay
Dose-Response Relationship
Drug
04 agricultural and veterinary sciences
Cell Biology
Hyperplasia
medicine.disease
Rats
030104 developmental biology
Endocrinology
Gene Expression Regulation
Dysplasia
Benzamides
Pyrazoles
Activin Receptors
Type I
Receptors
Transforming Growth Factor beta
Signal Transduction
Zdroj: Toxicologic Pathology. 35:284-295
ISSN: 1533-1601
0192-6233
Popis: 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.
Databáze: OpenAIRE
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