Endoplasmic Reticulum Stress-Unfolding Protein Response-Apoptosis Cascade Causes Chondrodysplasia in a col2a1 p.Gly1170Ser Mutated Mouse Model

Abstract

The collagen type II alpha 1 (COL2A1) mutation causes severe skeletal malformations, but the pathogenic mechanisms of how this occurs are unclear. To understand how this may happen, a col2a1 p.Gly1170Ser mutated mouse model was constructed and in homozygotes, the chondrodysplasia phenotype was observed. Misfolded procollagen was largely synthesized and retained in dilated endoplasmic reticulum and the endoplasmic reticulum stress (ERS)-unfolded protein response (UPR)-apoptosis cascade was activated. Apoptosis occurred prior to hypertrophy, prevented the formation of a hypertrophic zone, disrupted normal chondrogenic signaling pathways, and eventually caused chondrodysplasia. Heterozygotes had normal phenotypes and endoplasmic reticulum stress intensity was limited with no abnormal apoptosis detected. Our results suggest that earlier chondrocyte death was related to the ERS-UPR-apoptosis cascade and that this was the chief cause of chondrodysplaia. The col2a1 p.Gly1170Ser mutated mouse model offered a novel connection between misfolded collagen and skeletal malformation. Further investigation of this mouse mutant model can help us understand mechanisms of type II collagenopathies.

Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity

“…Activation of the UPR typically results in reduced chondrocyte proliferation, increased apoptosis, or altered differentiation, culminating in the observed short stature and deformities of the face and joints in many types of chondrodysplasia (Patterson and Dealy, 2014). For instance, a key glycine to serine mutation in collagen 2A1 results in shortening of the femurs and humeri, suggesting disruptions in endochondral bone ossification (Liang et al, 2014). Researchers observed significant increases in the gene expression of UPR mediators, decreased proliferation and increased apoptosis resulting in elimination of the hypertrophic zone of developing endochondral bones (Liang et al, 2014).…”

“…For instance, a key glycine to serine mutation in collagen 2A1 results in shortening of the femurs and humeri, suggesting disruptions in endochondral bone ossification (Liang et al, 2014). Researchers observed significant increases in the gene expression of UPR mediators, decreased proliferation and increased apoptosis resulting in elimination of the hypertrophic zone of developing endochondral bones (Liang et al, 2014). …”

Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

“…, Fabry’s and Gaucher’s diseases (Yam et al 2006; Maor et al 2013; Ron et al 2010); and in the pathology of diseases involving professional secretory tissues such as cystic fibrosis and α1-antitrypsin deficiency (Bartoszewski et al 2011; Alam et al 2014). Recent reports investigating effects of mutations on assembly and secretion of several ECM components suggest that multiple outcomes such as misfolding and intracellular accumulation of mutant ECM proteins may result from induction of ER stress (Chung et al 2009; Liang et al 2014; Rajpar et al 2009; Pieri et al 2014; Firtina et al 2009; Gould et al 2007; Nugent et al 2009; Bateman et al 2009; Boot-Handford and Briggs 2010; Yang et al 2005). …”

“…Although individually rare, they cause a significant impact on the quality of life for patients suffering from skeletal abnormalities. Genes encoding cartilage ECM proteins affected by mutations which disrupt growth plate differentiation comprise collagen types II, IX, X, and XI; aggrecan; cartilage oligomeric matrix protein (COMP); and matrilin 3 (Hintze et al 2008; Chung et al 2009; Liang et al 2014; Ho et al 2007; Mäkitie et al 2010; Kuivaniemi et al 1997; Warman et al 2011; Bateman et al 2009; Boot-Handford and Briggs 2010; Yang et al 2005; Briggs et al 2015). The list of collagenopathies associated with mutations in collagen types II and X is presented in Table 1.…”

“…In recent years, accumulating evidence indicates that abnormal folding and accumulation of structural proteins that are produced to fulfil their physiological function in the extracellular space of tissues may lead to ER stress and induction of a wide range of systemic diseases. For instance, several reports linked ER stress to mutations in collagen type II that induce various forms of spondyloepiphyseal dysplasia (SED) (Chung et al 2009; Okada et al 2015; Liang et al 2014). Other studies highlight the role of ER stress in the pathogenesis of metaphyseal (chondro) dysplasia, Schmid type (MCDS), a disorder caused by mutations in the collagen type X, characterized by expansion of the hypertrophic zone of the growth plate resulting in dwarfism (Rajpar et al 2009; Ho et al 2007; Mäkitie et al 2010).…”