Life science
Medical & healthcare, Drug development

Osteoblast-derived vesicles induce a switch frombone-formation to bone-resorption
Department of Immunology and Cell Biology, Graduate School of Medicine
Specially Appointed Assistant Professor Maki Uenaka

https://researchmap.jp/umakiLife science

Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences
Associate Professor Junichi Kikuta

https://researchmap.jp/jkikuta

Professor Masaru Ishii

https://researchmap.jp/read0076684

Abstract
Osteoblasts act in a group to make bone over the course of several months. However, how osteoblasts cooperate with each otherin vivo is still unknown. We established an advanced high-resolution microscopy system to visualize extracellular vesicles secreted
and captured by mature osteoblasts in vivo and identified a subset
of osteoblast-derived vesicles limiting bone formation and stimulating bone-resorbing osteoclast differentiation through a microRNA(miRNA)-mediated mechanism. The osteoblast communication
via extracellular vesicles controls the dynamic transition frombone-forming to bone-resorbing phases in vivo and could be a target for new treatments for bone diseases.

lular vesicles from bone-making osteoblasts is a key factor for theswitching through a microRNA-mediated mechanism. The osteoblast communication via extracellular vesicles controls the dynamictransition from bone-forming to bone-resorbing phases in vivo andcould be a target for new treatments for bone diseases.

▍ Background & Results
Bone remodeling occurs in different parts of the body throughout
life to maintain bone architecture balance and systemic mineral
homeostasis. During this “remodeling” process, osteoclasts remove mineralized bones, whereas osteoblasts form new bones.
These resorption and formation phases are linked and balancedwith intermittent coupling phases. Functional coupling between
these two cell types is critical for the maintenance of proper bonemetabolism, and the mechanisms controlling the transition frombone-resorbing to bone-forming phases have been investigated.
Nevertheless, the molecular and cellular mechanisms terminating
osteoblastic bone formation and promoting osteoclastic bone resorption remain elusive.

Fig.1 A, Schematic showing intravital imaging analysis of skull bone of mice.
Cyan shows osteoblasts and their extracellular vesicles; blue shows bone tissue.
B, Representative consecutive images of osteoblast vesicles released and captured by osteoblasts.

Intravital optical imaging using multiphoton microscopy can help
dissect in vivo cellular dynamics in various intact tissues and organs. To understand the spatiotemporal dynamics of bone remodeling in vivo, we have established an intravital imaging techniqueto visualize the intact bone tissues of living mice. Using this method, we explored the interplay between bone-destroying osteoclasts
and bone-forming osteoblasts. However, the spatial resolution of intravital bone imaging was insufficient to visualize structures smaller
than cells.
We established an advanced high-resolution microscopy system
to visualize extracellular vesicles secreted and captured by mature
osteoblasts in vivo and identified a subset of osteoblast-derived
vesicles limiting bone formation and stimulating osteoclast differentiation, thus regulating the switch from bone formation to bone
resorption through a microRNA (miRNA)-mediated mechanism.

▍ Significance of the research and Future perspective
What determines to switch bone formation to resorption has still
been unclear. We showed intercellular communication via extracel-Fig. 2 A, Representative images of Alizarin Red S staining showing calcificationof osteoblasts treated with or without vesicles. Red: calcification. Scale bar: 200μm. B, Representative image of mature osteoclasts among osteoclast precursors
co-cultured with vesicle-treated osteoblasts or control osteoblasts. Red: mature
osteoclast. Scale bar: 100 µm. C, Interactions among mOBs via SOVs inhibit osteoblastic bone formation and stimulate osteoclast formation, thus switching fromthe bone formation phase to the bone resorption phase.

P a t e n t
Uenaka, Maki; Kikuta, Junichi; Ishii, Masaru et al. Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo. Naturecommunications. 2022,13 (1), 1066-1066, doi: 10.1038/s41467-022-28673-2
UR
L http://www.icb.med.osaka-u.ac.jp/english/index.html
K e y w o r d bone metabolism, intravital imaging, extracellular vesicle, osteoblast, osteoclast
Tr e a t i s e