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

Stein, Merle; Barnea-Zohar, Maayan; Shalev, Moran; Arman, Esther; Brenner, Ori; Winograd‐Katz, Sabina; Gerstung, Jennifer; Thalji, Fadi; Kanaan, Moien; Elinav, Hila; Stepensky, Polina; Geiger, Benjamin; Tuckermann, Jan; Elson, Ari

doi:10.1016/j.bone.2020.115360

Cited by 12 publications

(26 citation statements)

References 32 publications

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“…These include inability to bind specific phospholipids, decreased endocytosis, absence of ruffled borders, and lack of acidification capability (Figs. 3E, 3F and 4D in this study and (Stein et al, 2020)). Consistent with the reported role of sorting nexins in phospholipid binding and membrane trafficking (Cullen, 2008;van Weering et al, 2010) we show here that wild-type SNX10 binds PI3P and PI(3,5)P 2 while R51Q SNX10 lacks this capacity (Fig.…”

Section: Discussionsupporting

confidence: 69%

“…In order to examine the cellular and whole-organism manifestations of the R51Q mutation in SNX10 we recently generated knock-in mice bearing this mutation (Stein et al, 2020).…”

Section: Journal Of Cell Science • Accepted Manuscriptmentioning

confidence: 99%

“…Cells were then either fixed and fluorescently labeled for actin, tubulin, and DNA, or were subjected to live-cell video microscopy using phase contrast or interference reflection microscopy (IRM) optics. Splenocytes were used for these experiments since the massive osteopetrosis of RQ/RQ mice radically reduced the bone cavity volume and prevented isolation of sufficient bone marrow cells for routine OCL preparation (Stein et al, 2020).…”

Section: Cultured Rq/rq Ocls Are Gigantic and Unstablementioning

confidence: 99%

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An SNX10-dependent mechanism downregulates fusion between mature osteoclasts

Barnea-Zohar

Winograd‐Katz

Shalev

et al. 2021

Journal of Cell Science

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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 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 10-100 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 down-regulates 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.

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Section: Discussionsupporting

confidence: 69%

“…In order to examine the cellular and whole-organism manifestations of the R51Q mutation in SNX10 we recently generated knock-in mice bearing this mutation (Stein et al, 2020).…”

Section: Journal Of Cell Science • Accepted Manuscriptmentioning

confidence: 99%

Section: Cultured Rq/rq Ocls Are Gigantic and Unstablementioning

confidence: 99%

See 1 more Smart Citation

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts

Barnea-Zohar

Winograd‐Katz

Shalev

et al. 2021

Journal of Cell Science

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“…Similar observations were made in other models of osteopetrosis despite demonstrably low OCL activity (e.g., Neutzsky-Wulff et al, 2008;Stein et al, 2020), indicating that circulating CTX levels might not accurately reflect in vivo OCL activity in these cases. Bone formation, as assessed by the clinical marker P1NP, was unaltered.…”

Section: Mouse Models Of Snx10 Mutations In Arosupporting

confidence: 73%

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

Elson

Stein

Rabie

et al. 2021

Front. Cell Dev. Biol.

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Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such “error of nature,” namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis.

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“…Consistently, the osteopetrotic phenotype is recapitulated in mice lacking SNX10 (SNX10−/−) owing to defects in osteoclast bone resorption function (Ye et al, 2015; Zhou et al, 2016). Similarly, mimicking the phenotype of human mutation R51Q of SNX10 with ARO (Aker et al, 2012), SNX10 R51Q knock‐in mouse model manifest severe osteopetrosis with mutant osteoclasts exhibiting a lack of bone resorption capability and impaired proton pump activity (Stein et al, 2020).…”

Section: The Role Of Snx10 In Skeletal Biologymentioning

confidence: 98%

The molecular structure and function of sorting nexin 10 in skeletal disorders, cancers, and other pathological conditions

Qiu

Zhao

et al. 2020

Journal Cellular Physiology

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SNX10 is a member of the phox homology domain-containing family of phosphoinositidebinding proteins. Intracellularly, SNX10 localizes to endosomes where it mediates intracellular trafficking, endosome organization, and protein localization to the centrosome and cilium. It is highly expressed in bone and the gut where it participates in bone mineral and calcium homeostasis through the regulation of osteoclastic bone resorption and gastric acid secretion, respectively. Not surprisingly, patients harboring mutations in SNX10 mutation manifest a phenotype of autosomal recessive osteopetrosis or malignant infantile osteopetrosis, which is clinically characterized by dense bones with increased cortical bone into the medullary space with bone marrow occlusion or depletion, bone marrow failure, and anemia. Accordingly, SNX10 mutant osteoclasts exhibit impaired bone resorptive capacity. Beyond the skeleton, there is emerging evidence implicating SNX10 in cancer development, metabolic disorders, inflammation, and chaperone-mediated autophagy. Understanding the structural basis through which SNX10 exerts its diverse biological functions in both cell and tissue-specific manners may therefore inform new therapeutic opportunities toward the treatment and management of SNX10-related diseases.

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

Cited by 12 publications

References 32 publications

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts

Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis

The molecular structure and function of sorting nexin 10 in skeletal disorders, cancers, and other pathological conditions

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