title: Premature chondrocyte apoptosis and compensatory upregulation of chondroregulatory protein expression in the growth plate of Goto-Kakizaki diabetic rats.
abstract: Type 2 diabetes mellitus (T2DM) is much more detrimental to bone than previously thought. Specifically, it is associated with aberrant bone remodeling, defective bone microstructure, poor bone quality, and growth retardation. The T2DM-associated impairment of bone elongation may result from a decrease in growth plate function, but the detailed mechanism has been unknown. The present study, therefore, aimed to test hypothesis that T2DM led to premature apoptosis of growth plate chondrocytes in Goto-Kakizaki (GK) type 2 diabetic rats, and thus triggered the compensatory responses to overcome this premature apoptosis, such as overexpression of Runt-related transcription factor (Runx)-2 and vascular endothelial growth factor (VEGF), the essential mediators for bone elongation. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) of epiphyseal sections successfully revealed increases in chondrocyte apoptosis in the hypertrophic zone (HZ) and chondro-osseous junction of GK rats. Quantitative immunohistochemical analysis further confirmed the overexpression of parathyroid hormone-related protein (PTHrP), Runx2 and VEGF, but not Indian hedgehog (Ihh) in the HZ. Analysis of blood chemistry indicated suppression of bone remodeling with a marked decrease in parathyroid hormone level. In conclusion, GK rats manifested a premature increase in chondrocyte apoptosis in the HZ of growth plate, and a compensatory overexpression of chondroregulatory proteins, such as PTHrP, Runx2, and VEGF. Our results, therefore, help explain how T2DM leads to impaired bone elongation and growth retardation.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Ratchaneevan
authors.initials: R
authors.lastname: Aeimlapa
authors.affiliation: Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand; Office of Academic Management, Faculty of Allied Health Sciences, Burapha University, Chonburi, Thailand. Electronic address: kannikar@buu.ac.th.
authors.forename: Kannikar
authors.initials: K
authors.lastname: Wongdee
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Narattaphol
authors.initials: N
authors.lastname: Charoenphandhu
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Panan
authors.initials: P
authors.lastname: Suntornsaratoon
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Nateetip
authors.initials: N
authors.lastname: Krishnamra
mesh_terms: D000818:Animals; D017209:Apoptosis; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D053823:Hedgehog Proteins; C550919:Ihh protein, rat; D044162:Parathyroid Hormone-Related Protein; C493717:Runx2 protein, rat; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat
keywords: Chondrocyte apoptosis; Growth plate; Longitudinal bone growth; Type 2 diabetes mellitus (T2DM); Vascular endothelial growth factor (VEGF)