Characterization of a Sh3bp2 knock-in mouse: A model for cherubism

Date of Completion

January 2008


Biology, Genetics




Cherubism is a human genetic disorder that affects children around the ages of 3-4 years. It causes bilateral, symmetrical expansion of the jaws with thinning of the cortices and degradation of bone. Bone is replaced by proliferating stromal and fibrous tissue. The gene for cherubism is SH3BP2. Several point mutations in this adaptor protein have been found in cherubic patients. The underlying pathogenesis and effects of SH3BP2 mutations in causing cherubism has been an open ended question in the field of bone biology. ^ Sh3bp2 knock-in mice were developed with the intention of answering some of the mechanistic questions regarding the effects of Sh3bp2 Pro416Arg mutation (Pro418Arg in humans). It has been shown previously that these mice have increased osteoclast activity. In this thesis, we have examined the effects of Sh3bp2 mutation on osteoblasts and bone homeostasis. ^ Cherubism knock-in mice have an overall osteopenic phenotype. During their initial developmental stages, there is failure to thrive in the mutant animals. There is significant loss of bone volume fraction, trabecular number and increase in trabecular spacing in all the bones we examined. There is a significant decrease in the bone mineral density and bone mineral content in the femurs, skull and mandibles of these mice. There is an osteoblast functional defect as observed by a significant decrease in bone formation rate, mineral apposition rate and reduced amounts of osteoid formation and thickness in the trabecular bone. There is an apparent defect in the matrix produced by these osteoblasts which was examined by Fourier transformed infrared spectroscopy analysis. Differentiation of calvarial osteoblasts is also affected by a decrease in the early osteoblast differentiation markers like type I collagen, alkaline phosphatase, and osteocalcin. ^ In summary, Sh3bp2 knock-in mice exhibit a defect in bone formation, and homeostasis and this defect is likely to be a combination of both abnormal osteoclast and osteoblast function. In this study the effects on bone formation and osteoblast function have been described for the first time. ^