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

Abstract

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.

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

“…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 ).…”