Publications by authors named "Fadi Thalji"

2 Publications

  • Page 1 of 1

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts.

J Cell Sci 2021 May 11;134(9). Epub 2021 May 11.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.

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.
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http://dx.doi.org/10.1242/jcs.254979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182410PMC
May 2021

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

Bone 2020 07 8;136:115360. Epub 2020 Apr 8.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.
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http://dx.doi.org/10.1016/j.bone.2020.115360DOI Listing
July 2020