TY - JOUR
T1 - The inhibitory role of rab11b in osteoclastogenesis through triggering lysosome-induced degradation of c-fms and rank surface receptors
AU - Tran, Manh Tien
AU - Okusha, Yuka
AU - Feng, Yunxia
AU - Morimatsu, Masatoshi
AU - Wei, Penggong
AU - Sogawa, Chiharu
AU - Eguchi, Takanori
AU - Kadowaki, Tomoko
AU - Sakai, Eiko
AU - Okamura, Hirohiko
AU - Naruse, Keiji
AU - Tsukuba, Takayuki
AU - Okamoto, Kuniaki
N1 - Funding Information:
Funding: This research was funded by JSPS KAKENHI Grant Number JP16K11863 (K.O.).
PY - 2020/12/2
Y1 - 2020/12/2
N2 - Rab11b, abundantly enriched in endocytic recycling compartments, is required for the establishment of the machinery of vesicle trafficking. Yet, no report has so far characterized the biological function of Rab11b in osteoclastogenesis. Using in vitro model of osteoclasts differentiated from murine macrophages like RAW-D cells or bone marrow-derived macrophages, we elucidated that Rab11b served as an inhibitory regulator of osteoclast differentiation sequentially via (i) abolishing surface abundance of RANK and c-Fms receptors; and (ii) attenuating nuclear factor of activated T-cells c1 (NFATc-1) upstream signaling cascades, following RANKL stimulation. Rab11b was localized in early and late endosomes, Golgi complex, and endoplasmic reticulum; moreover, its overexpression enlarged early and late endosomes. Upon inhibition of lysosomal function by a specific blocker, chloroquine (CLQ), we comprehensively clarified a novel function of lysosomes on mediating proteolytic degradation of c-Fms and RANK surface receptors, drastically ameliorated by Rab11b overexpression in RAW-D cell-derived osteoclasts. These findings highlight the key role of Rab11b as an inhibitor of osteoclastogenesis by directing the transport of c-Fms and RANK surface receptors to lysosomes for degradation via the axis of early endosomes-late endosomes-lysosomes, thereby contributing towards the systemic equilibrium of the bone resorption phase.
AB - Rab11b, abundantly enriched in endocytic recycling compartments, is required for the establishment of the machinery of vesicle trafficking. Yet, no report has so far characterized the biological function of Rab11b in osteoclastogenesis. Using in vitro model of osteoclasts differentiated from murine macrophages like RAW-D cells or bone marrow-derived macrophages, we elucidated that Rab11b served as an inhibitory regulator of osteoclast differentiation sequentially via (i) abolishing surface abundance of RANK and c-Fms receptors; and (ii) attenuating nuclear factor of activated T-cells c1 (NFATc-1) upstream signaling cascades, following RANKL stimulation. Rab11b was localized in early and late endosomes, Golgi complex, and endoplasmic reticulum; moreover, its overexpression enlarged early and late endosomes. Upon inhibition of lysosomal function by a specific blocker, chloroquine (CLQ), we comprehensively clarified a novel function of lysosomes on mediating proteolytic degradation of c-Fms and RANK surface receptors, drastically ameliorated by Rab11b overexpression in RAW-D cell-derived osteoclasts. These findings highlight the key role of Rab11b as an inhibitor of osteoclastogenesis by directing the transport of c-Fms and RANK surface receptors to lysosomes for degradation via the axis of early endosomes-late endosomes-lysosomes, thereby contributing towards the systemic equilibrium of the bone resorption phase.
KW - C-Fms
KW - NFATc-1
KW - Osteoclasts
KW - RANK
KW - Rab11b
KW - Vesicular transport
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U2 - 10.3390/ijms21249352
DO - 10.3390/ijms21249352
M3 - Article
C2 - 33302495
AN - SCOPUS:85097539218
VL - 21
SP - 1
EP - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 24
M1 - 9352
ER -