Cherubism gene Sh3bp2 is important for optimal bone formation, osteoblast differentiation, and function

Abstract

Introduction Cherubism is a human genetic disorder that causes bilateral symmetrical enlargement of the maxilla and mandible in children. It is caused by mutations in SH3BP2. The exact pathogenesis of the disorder is an area of active research. Sh3bp2 knock-in mice were developed by introducing a Pro416Arg mutation (Pro418Arg in humans) in the mouse genome. The osteoclast phenotype of this mouse model was recently described. Methods We examined the bone phenotype of the cherubism mouse model, the role of Sh3bp2 during bone formation, osteoblast differentiation and osteoblast function. Results We observed delays in early postnatal development of homozygous Sh3bp2KI/KI mice. Sh3bp2KI/KI mice exhibit increased growth plate thickness and significantly decreased trabecular bone thickness and reduced bone mineral density. Histomorphometric and μ-CT analyses reveal bone loss in cranial and appendicular skeleton. Sh3bp2KI/KI mice also exhibit a significant decrease in osteoid formation that indicates a defect in osteoblast function. Calvarial osteoblast cell cultures exhibit a decrease in alkaline phosphatase expression and mineralization suggesting reduced differentiation potential. Gene expression of osteoblast differentiation markers like collagen type-I, alkaline phosphatase and osteocalcin are decreased in osteoblast cultures from Sh3bp2KI/KI mice. Conclusions These data suggest that Sh3bp2 function regulates bone homeostasis not only through osteoclast-specific effects but also through effects on osteoblast differentiation and function.

Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties

“…This finding of reduced mineralization and reduced pOBCol2.3GFP activity in vitro is consistent with our in vivo studies. The observation of increased osteoid formation in bone of Sh3bp2 KI/KI mice [30] is further consistent with undermineralized bone matrix in this model.…”

Clinical care of children with sterile bone inflammation

“…It is transmitted in an autosomal dominant pattern with 100% penetrance in men and 50-70% in women [84,85]. Novel mutations in the binding protein SH3BP2 encoding gene on chromosome 4p16.3 have been detected in cherubism patients [86,87]. Radiographic lesions often begin near the angle of the mandible and spread to the mandibular ramus and body and appear as cystic multilocular radiolucencies [84,88,89].…”

Genetics of Cherubism

“…Following the appearance of the first symptoms and diagnosis of the condition, manifestations of the lesions increase for the first two years and begin to stabilize or even regress to a stop when the child reaches puberty. Pain-free, cyst-like structures develop and substitute for bone as the upper and lower jaws expand [5][6][7]8].…”