Deregulation of osteoclastogenesis in osteopetrotic mice: From point mutation (R51Q) in SNX10 gene to the formation of giant non-functional osteoclasts
2Depatment of Molecular Genetics, Weizmann Institute of Science, Israel
Osteoclasts (OCLs) are multinucleated cells involved in bone resorption, which, together with bone-forming osteoblasts, regulate bone remodeling and homeostasis. Previous studies demonstrated that specific mutation (R51Q) in sorting nexin 10 (SNX10) leads to Autosomal Recessive Osteopetrosis (ARO), a severe pathological state manifested by the formation of excessively dense bone due to OCLs’ failure to resorb bone. To understand the role of SNX10 in OCLs’ activity, we generated knock-in mice bearing the R51Q SNX10 mutation, which was shown to be present in human ARO patients. Homozygous R51Q SNX10 mice resemble in many aspects the phenotype of human patients1. This study investigates the cell-autonomous phenotype of SNX10 R51Q mutation under culture conditions2.
Surprisingly, we discovered that R51Q SNX10 mutation leads to aberrant osteoclastogenesis, whereby cells undergo deregulated fusion and differentiate into gigantic multinucleated cells, 10-100 fold larger than their wild-type counterparts. Time-lapse movies of the differentiating mutant and wild-type (WT) OCLs indicated that mature WT OCLs do not fuse, while the mutant cells continue to fuse, forming gigantic, non-functional cells and then die2. We show here that the fusion dynamics of mutant osteoclasts differ from wild-type controls and shed new light on the physiological regulation of osteoclastogenesis and its deregulation in “osteopetrotic osteoclasts.”
1 PMID: 32278070
2 PMCID: PMC8182410