Massive osteopetrosis caused by giant, non-functional osteoclasts in R51Q SNX10 mutant mice

In this study we report on the establishment and characterization of a novel knock-in mouse model that is homozygous for the R51Q mutation in the sorting nexin 10 (SNX10) protein. This mutation leads to massive, early-onset, and widespread osteopetrosis in the mutant mice, similar to that observed in humans who are homozygous for this mutation. The diseased mice exhibit multiple additional characteristics of the corresponding human osteopetrosis, including missing and impacted teeth, occasional osteomyelitis, stunted growth, failure to thrive, and a significantly-reduced lifespan. The phenotype of homozygous R51Q SNX10 osteoclasts is unique and defines a novel form of ARO that combines both lack of bone-resorbing activity and reduced cell numbers in vivo. Furthermore, mutant osteoclasts grown on bone develop a giant cell morphology, reaching sizes that are up to three orders of magnitude larger than osteoclasts from wild-type or heterozygous mice. These large osteoclasts display poor survival in vitro, which may account for their fewer numbers in vivo. Electron microscopy studies indicate that homozygous mutant osteoclasts exhibit severely impaired ruffled borders and are incapable of resorbing bone, providing a clear cellular basis for the osteopetrotic phenotype. We propose that the R51Q SNX10 mutation directly causes osteoporosis by affecting both osteoclast formation and function. We further conclude that the maximal size of osteoclasts is determined by an active and genetically-regulated mechanism in which SNX10 participates, and that it is disrupted by the R51Q SNX10 mutation. Note: MB and MS contributed equally to this study. Correspondence should be addressed to JT or AE.