title: A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth.
abstract: Disease mechanisms leading to different forms of chondrodysplasia include extracellular matrix (ECM) alterations and intracellular stress resulting in abnormal changes to chondrocyte proliferation and survival. Delineating the relative contribution of these two disease mechanisms is a major challenge in understanding disease pathophysiology in genetic skeletal diseases and a prerequisite for developing effective therapies. To determine the influence of intracellular stress and changes in chondrocyte phenotype to the development of chondrodysplasia, we targeted the expression of the G2320R mutant form of thyroglobulin to the endoplasmic reticulum (ER) of resting and proliferating chondrocytes. Previous studies on this mutant protein have shown that it induces intracellular aggregates and causes cell stress and death in the thyroid gland. The expression and retention of this exogenous mutant protein in resting and proliferating chondrocytes resulted in a chronic cell stress response, growth plate dysplasia and reduced bone growth, without inducing any alterations to the architecture and organization of the cartilage ECM. More significantly, the decreased bone growth seemed to be the direct result of reduced chondrocyte proliferation in the proliferative zone of growth plates in transgenic mice, without transcriptional activation of a classical unfolded protein response (UPR) or apoptosis. Overall, these data show that mutant protein retention in the ER of resting and proliferative zone chondrocytes is sufficient to cause disrupted bone growth. The specific disease pathways triggered by mutant protein retention do not necessarily involve a prototypic UPR, but all pathways impact upon chondrocyte proliferation in the cartilage growth plate.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Gualeni
authors.forename: M Helen
authors.initials: MH
authors.lastname: Rajpar
authors.forename: Aaron
authors.initials: A
authors.lastname: Kellogg
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bell
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000818:Animals; D017209:Apoptosis; D001846:Bone Development; D049109:Cell Proliferation; D019902:Chondrocytes / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006132:Growth Plate / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014158:Transcription, Genetic
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