Pathological ER stress impairs osteocyte maturation causing hyperostosis in mice

Abstract

Bone formation and maintenance depend on the balance between bone matrix synthesis and degradation. Shift of this balance may lead to pathological conditions such as osteoporosis or hyperostosis. Osteoblasts on bone surface are active in bone synthesis and some of them will become embedded in bone matrix and differentiate into osteocytes with distinct morphological and molecular changes. Osteocytes have roles in mineralizing bone matrix, sensing mechanical stimuli and regulating differentiation and activity of osteoblasts residing at the bone surface through the action of Sclerostin (Sost), an inhibitor of WNT signaling. We showed in a transgenic mouse model with the activation of endoplasmic reticulum (ER) stress in early differentiating osteocytes delays the maturation process with impaired Sost expression leading to generalize hyperostosis resembling human craniodiaphyseal dysplasia (CDD). A clear relationship between the activation of the unfolded protein response and the onset of hyperostosis was established. The onset of hyperostosis was suppressed by a treatment with sodium 4-phenobutyrate (4-PBA), a chemical chaperone assisting protein folding. We propose that ER homeostasis is critical for osteocyte differentiation and function, and that ER stress in osteocytes of CDD patients with heterozygous mutations in SOST with impaired secretion could be part of the disease mechanism, and chemical chaperones may be considered as a therapeutic agent.