Hematopoietic cytoplasmic adaptor protein Hem1 promotes osteoclast fusion and bone resorption in mice

Wang, Xiaoyan; Shao, Longquan; Richardson, Kimberly; Wen, Li; Warren, Aaron; Krager, Kimberly J.; Aykin-Burns, Nūkhet; Hromas, Robert; Zhou, Daohong; Almeida, Maria; Kim, Ha‐Neui

doi:10.1016/j.jbc.2022.102841

Cited by 4 publications

(5 citation statements)

References 49 publications

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“…Mice lacking Hem1 showed a growth delay and reduced femoral length (Fig. 1 A), which is in accordance with previous studies 17 , 30 . Microtomography (µCT) analysis of distal femora revealed that Hem1 -/- mice develop a high bone mass phenotype (Fig.…”

Section: Resultssupporting

confidence: 93%

“…This is in some contrast to a recent study by Wang et al who also observed a resorption defect due to Hem1 deletion, but also a reduced osteoclast differentiation due to impaired fusion in vitro . However, consistent with our observations, their Hem1-deleted mice showed an osteopetrotic phenotype with an increased number of osteoclasts, which is not indicative of reduced osteoclast differentiation and suggests that the contrasting in vitro results are rather caused by different experimental settings 30 .…”

Section: Discussionsupporting

confidence: 88%

“…However, consistent with our observations, their Hem1-deleted mice showed an osteopetrotic phenotype with an increased number of Vol:. ( 1234567890 www.nature.com/scientificreports/ osteoclasts, which is not indicative of reduced osteoclast differentiation and suggests that the contrasting in vitro results are rather caused by different experimental settings 30 . Indeed, in line with our observation, osteoclast-specific deletion of Rac1/Rac2 results in abnormal high numbers of osteoclasts in vivo and in vitro 50 , further underlining that Hem1-deletion does not disturb osteoclast precursor proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…While the role of the Arp2/3 complex and WASP has long been recognized 28 , 29 , the WRC has only recently been linked to osteoclast development. Although Wang et al have shown that the absence of Hem1 in mice leads to osteopetrosis due to a defect in osteoclast fusion and resorption 30 , the mechanism by which Hem1 is involved in the development and activity of osteoclasts still needs to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Hem1 is essential for ruffled border formation in osteoclasts and efficient bone resorption

Werbenko,

de Gorter,

Kleimann

et al. 2024

Sci Rep

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Bone resorption is highly dependent on the dynamic rearrangement of the osteoclast actin cytoskeleton to allow formation of actin rings and a functional ruffled border. Hem1 is a hematopoietic-specific subunit of the WAVE-complex which regulates actin polymerization and is crucial for lamellipodia formation in hematopoietic cell types. However, its role in osteoclast differentiation and function is still unknown. Here, we show that although the absence of Hem1 promotes osteoclastogenesis, the ability of Hem1-/- osteoclasts to degrade bone was severely impaired. Global as well as osteoclast-specific deletion of Hem1 in vivo revealed increased femoral trabecular bone mass despite elevated numbers of osteoclasts in vivo. We found that the resorption defect derived from the morphological distortion of the actin-rich sealing zone and ruffled border deformation in Hem1-deficient osteoclasts leading to impaired vesicle transport and increased intracellular acidification. Collectively, our data identify Hem1 as a yet unknown key player in bone remodeling by regulating ruffled border formation and consequently the resorptive capacity of osteoclasts.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hem1 is essential for ruffled border formation in osteoclasts and efficient bone resorption

Werbenko,

de Gorter,

Kleimann

et al. 2024

Sci Rep

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show abstract

“…Hem1 deficient osteoclasts developed normally but exhibited impaired fusion into multinucleated osteoclasts and diminished mitogen-activated protein kinase and tyrosine kinase c-Abl activity, resulting in reduced bone resorption. These findings highlight the crucial role of Hem1 in osteoclast differentiation and preserving normal bone mass ( 109 , 110 ).…”

Section: Murine Models Of Hem1 Deficiencymentioning

confidence: 63%

Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans

Christodoulou,

Tsai,

Suwankitwat

et al. 2024

Front. Immunol.

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Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.

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Drug Resistance, Characterization and Phylogenetic Discrepancy of Salmonella enterica Isolates from Distinct Sources

Indrajith

Natarajan²,

Selvankumar³

et al. 2023

Curr Microbiol

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Hematopoietic cytoplasmic adaptor protein Hem1 promotes osteoclast fusion and bone resorption in mice

Cited by 4 publications

References 49 publications

Hem1 is essential for ruffled border formation in osteoclasts and efficient bone resorption

Hem1 is essential for ruffled border formation in osteoclasts and efficient bone resorption

Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans

Drug Resistance, Characterization and Phylogenetic Discrepancy of Salmonella enterica Isolates from Distinct Sources

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