R51Q SNX10 induces osteopetrosis and uncontrolled fusion of monocytes to form giant, non-functional osteoclasts

Bone-resorbing osteoclasts are formed by fusion of monocyte/macrophage precursor cells. Normally, fusion is limited and osteoclasts have a defined size range, but the mechanism that regulates fusion and halts it when appropriate is unknown. We show that mice homozygous for the R51Q mutation in the endosomal trafficking-associated protein SNX10, which has been linked with autosomal recessive osteopetrosis in humans, are massively osteopetrotic due to reduced numbers of osteoclasts that are also structurally-defective and inactive. R51Q SNX10 osteoclasts fuse rapidly and continuously in culture to form giant, unstable cells that continue to fuse and grow ever larger in size, and which are unique to this mutant. In particular, mature osteoclasts, which normally do not fuse with each other, fuse readily in R51Q SNX10 cultures. Endocytosis, which has been shown to inhibit fusion in other cell types, is defective in R51Q SNX10 osteoclasts, suggesting that removal of fusogens or other cell-surface proteins is important for halting osteoclast fusion. Contrary to wild-type SNX10, R51Q SNX10 does not bind phospholipids, which causes its mis-localization, aggregation, and degradation. These results confirm R51Q SNX10 as a cause for osteopetrosis and show, for the first time, that osteoclast size is limited by an active, cell-autonomous molecular mechanism that operates by down-regulating cell fusion. SNX10 participates in this mechanism, and its function is blocked by the R51Q mutation that destabilizes the SNX10 protein.