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2016 ; 95
(6
): 673-9
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Characterization of Regulatory Extracellular Vesicles from Osteoclasts
#MMPMID26908631
Huynh N
; VonMoss L
; Smith D
; Rahman I
; Felemban MF
; Zuo J
; Rody WJ Jr
; McHugh KP
; Holliday LS
J Dent Res
2016[Jun]; 95
(6
): 673-9
PMID26908631
show ga
Extracellular vesicles (EVs), which include exosomes and ectosomes/microvesicles,
have emerged as important intercellular regulators. EVs can interact with surface
receptors of target cells and can transport luminal components, including
messenger RNAs (mRNAs), microRNAs, and enzymes, to the cytosol of the target
cell. Here, we show that hematopoietic cells grown in culture shed exosome-like
EVs as they differentiate from preosteoclasts into osteoclasts. These EVs were
between 25 and 120 nm (mean, 40 nm) in diameter determined by transmission
electron microscopy. The exosome-associated markers CD63 and EpCAM were enriched
in the isolated EVs while markers of Golgi and endoplasmic reticulum were not
detected. Treatment of isolated hematopoietic cells with EVs did not affect their
receptor activator of nuclear factor ?B-ligand (RANKL)-stimulated differentiation
into osteoclasts. However, EVs from osteoclast precursors promoted
1,25-dihydroxyvitamin D3-dependent osteoclast formation in whole mouse marrow
cultures, and EVs from osteoclast-enriched cultures inhibited osteoclastogenesis
in the same cultures. These data suggested that osteoclast-derived EVs are
paracrine regulators of osteoclastogenesis. EVs from mature osteoclasts contained
receptor activator of nuclear factor ?B (RANK). Immunogold labeling showed RANK
was enriched in 1 in every 32 EVs isolated from osteoclast-enriched cultures.
Depletion of RANK-rich EVs relieved the ability of osteoclast-derived EVs to
inhibit osteoclast formation in 1,25-dihydroxyvitamin D3-stimulated marrow
cultures. In summary, we show for the first time that EVs released by osteoclasts
are novel regulators of osteoclastogenesis. Our data suggest that RANK in EVs may
be mechanistically linked to the inhibition of osteoclast formation. RANK present
in EVs may function by competitively inhibiting the stimulation of RANK on
osteoclast surfaces by RANKL similar to osteoprotegerin. RANK-rich EVs may also
take advantage of the RANK/RANKL interaction to target RANK-rich EVs to
RANKL-bearing cells for the delivery of other regulatory molecules.
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