ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta

Abstract

Osteogenesis imperfecta is an inherited disorder characterized by increased bone fragility, fractures, and osteoporosis, and most cases are caused by mutations affecting the type I collagen genes. Here, we describe a new mouse model for Osteogenesis imperfecta termed Aga2 (abnormal gait 2) that was isolated from the Munich N-ethyl-N-nitrosourea mutagenesis program and exhibited phenotypic variability, including reduced bone mass, multiple fractures, and early lethality. The causal gene was mapped to Chromosome 11 by linkage analysis, and a C-terminal frameshift mutation was identified in the Col1a1 (procollagen type I, alpha 1) gene as the cause of the disorder. Aga2 heterozygous animals had markedly increased bone turnover and a disrupted native collagen network. Further studies showed that abnormal proa1(I) chains accumulated intracellularly in Aga2/þ dermal fibroblasts and were poorly secreted extracellularly. This was associated with the induction of an endoplasmic reticulum stress-specific unfolded protein response involving upregulation of BiP, Hsp47, and Gadd153 with caspases-12 and À3 activation and apoptosis of osteoblasts both in vitro and in vivo. These studies resulted in the identification of a new model for Osteogenesis imperfecta, and identified a role for intracellular modulation of the endoplasmic reticulum stress-associated unfolded protein response machinery toward osteoblast apoptosis during the pathogenesis of disease.

17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts

“…ER stress-induced apoptosis acts as a causative agent of osteoporosis. [22][23][24][25][26] Our observations indicated that 17b-E 2 may contribute to protective effects on ER stress-induced apoptosis in osteoblasts. Osteoporosis is a highly prevalent disease and results in massive costs both to the individual and to the society through associated fragility fractures.…”

“…[17][18][19][20][21] ER stressinduced apoptosis of osteoblasts has also been implicated in the pathogenesis of osteoporosis. [22][23][24][25][26] Our study found that the MC3T3-E1 cells, the mouse calvaria osteoblasts, were led into the decrease of cellular viability in response to ER stress. However, pretreatment with 17b-E 2 can increase the viability of osteoblasts in ER stress in a dose-dependent manner between 0.1 nM and 100 nM and the effects plateaued at 10 nM.…”

“…[1][2][3][4][5] ER stress has been implicated as a crucial mechanism of apoptosis in various cell death processes, including osteoblast apoptosis during the development of osteoporosis. [22][23][24][25][26] Protective effects of estrogen on apoptosis of various cells have been indicated. [32][33][34] However, it is not entirely clear if estrogen can protect osteoblasts against ER stress-induced apoptosis.…”

“…ER stress has been reported to be involved in apoptosis induction that occurs during various pathophysiological progresses, including osteoporosis. [22][23][24][25][26] The ER stress is generally activated in response to various stressful conditions, such as hypoxia, the accumulation of unfolded or misfolded proteins, the alterations of calcium homeostasis, low glucose levels and others. [8][9][10] Recent reports have shown that ER stress occurs during osteogenic differentiation.…”

“…22 ER stress-associated osteoblast apoptosis is one of the most predominant pathogenesis of osteoporosis. [23][24][25][26] Thus, an intriguing question in osteoblasts is an outcome of survival in ER stress. The balance between cell death responses and cell survival responses may decide the occurrence and development of osteoporosis.…”