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An SNX10-dependent mechanism downregulates fusion between mature osteoclasts
- Source :
- Journal of Cell Science, article-version (VoR) Version of Record
- Publication Year :
- 2021
- Publisher :
- The Company of Biologists Ltd, 2021.
-
Abstract
- Homozygosity for the R51Q mutation in sorting nexin 10 (SNX10) inactivates osteoclasts (OCLs) and induces autosomal recessive osteopetrosis in humans and in mice. We show here that the fusion of wild-type murine monocytes to form OCLs is highly regulated, and that its extent is limited by blocking fusion between mature OCLs. In contrast, monocytes from homozygous R51Q SNX10 mice fuse uncontrollably, forming giant dysfunctional OCLs that can become 10- to 100-fold larger than their wild-type counterparts. Furthermore, mutant OCLs display reduced endocytotic activity, suggesting that their deregulated fusion is due to alterations in membrane homeostasis caused by loss of SNX10 function. This is supported by the finding that the R51Q SNX10 protein is unstable and exhibits altered lipid-binding properties, and is consistent with a key role for SNX10 in vesicular trafficking. We propose that OCL size and functionality are regulated by a cell-autonomous SNX10-dependent mechanism that downregulates fusion between mature OCLs. The R51Q mutation abolishes this regulatory activity, leading to excessive fusion, loss of bone resorption capacity and, consequently, to an osteopetrotic phenotype in vivo. This article has an associated First Person interview with the joint first authors of the paper.<br />Summary: Fusion of monocytes to become bone-resorbing osteoclasts is limited by an SNX10-dependent cell-autonomous mechanism. Loss of SNX10 function deregulates fusion and generates giant inactive osteoclasts.
- Subjects :
- Mutant
Osteoclasts
Biology
medicine.disease_cause
Bone resorption
03 medical and health sciences
Myoblast fusion
Mice
0302 clinical medicine
Osteoclast
medicine
Animals
Bone Resorption
Bone
Cell fusion
Sorting Nexins
030304 developmental biology
0303 health sciences
Mutation
Invadopodia and Podosomes
Osteopetrosis
Cell Biology
medicine.disease
Cell biology
Sorting nexin
medicine.anatomical_structure
030220 oncology & carcinogenesis
SNX10
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 14779137 and 00219533
- Volume :
- 134
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....f834417c65332f85dc6395b470622136