Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia

Abstract

Bone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.

[Retracted] Exosome: Function and Application in Inflammatory Bone Diseases

“…Osteoblasts, derived by direct differentiation of bone marrow mesenchymal stem cells, are responsible for bone formation in bone remodeling in vivo. Runt-related transcription factor-2 (Runx2) and osterix (OSX) are specific transcription factors for all osteoblast proliferation and differentiation stages, facilitating skeletal formation by transactivating bone matrix protein genes, including collagen type I, osteocalcin, and osteopontin [ 96 , 97 ]. Exosomes in aseptic bone inflammation can affect osteoblast differentiation and activity in multiple ways by acting directly or indirectly on the Wnt signaling pathway or the expression of the transcription factors Runx2 and OSX ( Figure 4 ).…”

Novel actions of sclerostin on bone

“…Two patients with CDD were reported to harbour de novo heterozygous autosomal dominant mutations in SOST that introduced missense mutations in the sclerostin signal peptide cleavage site, preventing secretion of sclerostin protein from transfected cells in vitro (Kim et al 2011). Interestingly, it was recently reported that endoplasmic reticulum (ER) stress caused by retention of a mutant protein in the osteocyte was associated with a generalised progressive hyperostosis with similarities to CDD (Chan et al 2017). In this work, expression of a truncated variant of the collagen type X alpha 1 chain (Col10a1) gene in transgenic mice resulted in production of collagen X chains, which were poorly secreted from the cell.…”

The Pervasive Effects of ER Stress on a Typical Endocrine Cell: Dedifferentiation, Mesenchymal Shift and Antioxidant Response in the Thyrocyte

“…If the adaptive response fails, cells execute apoptosis. While much attention has been devoted to the study of the survival/death switch (2-4), a new response to ER stress has emerged, which consists in an inhibition of differentiation (5)(6)(7)(8)(9)(10)(11).…”

“…However, recent reports have contributed to the idea that adaptation does not necessarily mean full recovery of the preexisting function. Indeed, reprogramming gene expression to a less differentiated state after ER stress has been shown in a number of systems (5)(6)(7)(8)(9)(10)(11).…”