While studies of the adaptor SH3BP2 have implicated a role in receptor-mediated signaling in mast cells and lymphocytes, they have failed to identify its function or explain why SH3BP2 missense mutations cause bone loss and inflammation in patients with cherubism. We demonstrate that Sh3bp2 "cherubism" mice exhibit trabecular bone loss, TNF-alpha-dependent systemic inflammation, and cortical bone erosion. The mutant phenotype is lymphocyte independent and can be transferred to mice carrying wild-type Sh3bp2 alleles through mutant fetal liver cells. Mutant myeloid cells show increased responses to M-CSF and RANKL stimulation, and, through mechanisms of increased ERK 1/2 and SYK phosphorylation/activation, they form macrophages that express high levels of TNF-alpha and osteoclasts that are unusually large. M-CSF and RANKL stimulation of myeloid cells that overexpress wild-type SH3BP2 results in similar large osteoclasts. This indicates that the mutant phenotype reflects gain of SH3BP2 function and suggests that SH3BP2 is a critical regulator of myeloid cell responses to M-CSF and RANKL stimulation.

BackgroundDolphin® visual treatment objective (VTO) prediction software is routinely utilized by orthodontists during the treatment planning of orthognathic cases to help predict post-surgical soft tissue changes. Although surgical soft tissue prediction is considered to be a vital tool, its accuracy is not well understood in tow-jaw surgical procedures. The objective of this study was to quantify the accuracy of Dolphin Imaging’s VTO soft tissue prediction software on class III patients treated with maxillary advancement and mandibular setback and to validate the efficacy of the software in such complex cases.MethodsThis retrospective study analyzed the records of 14 patients treated with comprehensive orthodontics in conjunction with two-jaw orthognathic surgery. Pre- and post-treatment radiographs were traced and superimposed to determine the actual skeletal movements achieved in surgery. This information was then used to simulate surgery in the software and generate a final soft tissue patient profile prediction. Prediction images were then compared to the actual post-treatment profile photos to determine differences.ResultsDolphin Imaging’s software was determined to be accurate within an error range of +/− 2 mm in the X-axis at most landmarks. The lower lip predictions were most inaccurate.ConclusionsClinically, the observed error suggests that the VTO may be used for demonstration and communication with a patient or consulting practitioner. However, Dolphin should not be useful for precise treatment planning of surgical movements. This program should be used with caution to prevent unrealistic patient expectations and dissatisfaction.

No 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.

No abstract