Cherubism gene Sh3bp2 is important for optimal bone formation, osteoblast differentiation, and function.
BACKGROUND
Cherubism is a human genetic disorder that causes bilateral symmetrical enlargement of the maxilla and the 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 Sh3bp2(KI/KI) mice, which exhibited increased growth plate thickness and significantly decreased trabecular bone thickness and bone mineral density. Histomorphometric and microcomputed tomography analyses showed bone loss in the cranial and appendicular skeletons. Sh3bp2(KI/KI) mice also exhibited a significant decrease in osteoid formation that indicated a defect in osteoblast function. Calvarial osteoblast cell cultures had decreased alkaline phosphatase expression and mineralization, suggesting reduced differentiation potential. Gene expression of osteoblast differentiation markers such as collagen type I, alkaline phosphatase, and osteocalcin were decreased in osteoblast cultures from Sh3bp2(KI/KI) mice.


CONCLUSIONS
These data suggest that Sh3bp2 regulates bone homeostasis through not only osteoclast-specific effects, but also through effects on osteoblast differentiation and function.
Mukherjee
Padma M
PM
Department of Craniofacial Sciences, Division of Orthodontics, School of Dental Medicine, University of Connecticut, 263 Farmington Ave., Farmington, CT 06030-3705, USA.
Wang
Chiachien J
CJ
Chen
I-Ping
IP
Jafarov
Toghrul
T
Olsen
Bjorn R
BR
Ueki
Yasuyoshi
Y
Reichenberger
Ernst J
EJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D015519:Bone Density / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002636:Cherubism / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D024042:Collagen Type I; C484644:Sh3bp2 protein, mouse; D015675:Osteocalcin; D000469:Alkaline Phosphatase