Endoplasmic reticulum stress is induced in growth plate hypertrophic chondrocytes in G610C mouse model of osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a hereditary bone disorder most commonly caused by autosomal dominant mutations in genes encoding type I collagen. In addition to bone fragility, patients suffer from impaired longitudinal bone growth. It has been demonstrated that in OI, an accumulation of mutated type I collagen in the endoplasmic reticulum (ER) induces ER stress in osteoblasts, causing osteoblast dysfunction leading to bone fragility. We hypothesize that ER stress is also induced in the growth plate where bone growth is initiated, and examined a mouse model of dominant OI that carries a G610C mutation in the procollagen α2 chain. The results demonstrated that G610C OI mice had significantly shorter long bones with growth plate abnormalities including elongated total height and hypertrophic zone. Moreover, we found that mature hypertrophic chondrocytes expressed type I collagen and ER dilation was more pronounced compared to wild type littermates. The results from in vitro chondrocyte cultures demonstrated that the maturation of G610C OI hypertrophic chondrocytes was significantly suppressed and ER stress related genes were upregulated. Given that the alteration of hypertrophic chondrocyte activity often causes dwarfism, our findings suggest that hypertrophic chondrocyte dysfunction induced by ER stress may be an underlying cause of growth deficiency in G610C OI mice.

Fracture Healing in Collagen-Related Preclinical Models of Osteogenesis Imperfecta

“…Similarly, the G610C mice showed accelerated differentiation via increased hypertrophic zones. This is also reflective of a recently published study showing increased growth plate hypertrophic zones in G610C that are a result of defects in the maturation of hypertrophic chondrocytes . Therefore, it is possible that the increased cartilage content we see in the 1‐week G610C callus is a result of chondrocytes remaining hypertrophic for an extended period of time.…”

“…Interestingly, although G610C mice also showed a reduced proportion of immature cartilage, they showed no change in proliferative cartilage and a trending increase in hypertrophic cartilage proportion at 1 week post‐fracture. G610C growth plates have been previously shown to have increased hypertrophic zones due to suppressed maturation . This indicates that G610C callus cartilage also exhibits accelerated chondrocyte maturation that may be stalled at the hypertrophic stage, translating to a depletion of available chondrocytes but an increase in cartilage proportion.…”

Management of Endocrine Disease: Osteogenesis imperfecta: an update on clinical features and therapies

“…Because chondrocytes are characterized by the expression of fibrillar collagen type II and, upon becoming hypertrophic, of collagen type X, it is not clear how the alterations in type I collagen that cause OI negatively impact the biology and activity of these cells. However, Scheiber et al (45) showed recently that murine hypertrophic chondrocytes also express type I collagen and that, in the Col1a2 G610C/+ mouse model of OI, these cells in addition to osteoblasts had an abnormally large ER, which likely caused ER stress and a chondrocyte maturation defect. They also observed elongated growth plates, which translated into significantly shorter long bones (45).…”

“…However, Scheiber et al (45) showed recently that murine hypertrophic chondrocytes also express type I collagen and that, in the Col1a2 G610C/+ mouse model of OI, these cells in addition to osteoblasts had an abnormally large ER, which likely caused ER stress and a chondrocyte maturation defect. They also observed elongated growth plates, which translated into significantly shorter long bones (45). Therefore, at least in this mouse model of OI, dysfunctional hypertrophic chondrocytes contribute to short stature.…”

Mechanisms Underlying Bone Loss Associated with Gut Inflammation

“…In spite of the lack of evidence proving direct link between ER stress presented in IBD and bone disease, the promising effect of UPR in bone cells differentiation and functions has been investigated in multiple studies. Scheiber et al showed that G610C osteogenesis imperfecta mice had longitudinal bone growth retardation, characterized by accumulated hypertrophic chondrocytes expressing ER dilation, and mutated type I collagen which induce osteoblast dysfunction due to ER stress [170]. ER stress also reflects one of the promising therapeutic mechanisms during rheumatoid disease process.…”