TY - JOUR
T1 - Bone metastatic mammary tumor cell-derived extracellular vesicles inhibit osteoblast maturation via JNK signaling
AU - Uehara, Norihisa
AU - Shibusawa, Nobuhide
AU - Mikami, Yoshikazu
AU - Kyumoto-Nakamura, Yukari
AU - Sonoda, Soichiro
AU - Kato, Hiroki
AU - Yamaza, Takayoshi
AU - Kukita, Toshio
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/12
Y1 - 2023/12
N2 - The metastases of breast cancer to bone often cause osteolytic lesions not only by stimulating osteoclasts to resorb the bone but also by inhibiting osteoblasts from bone formation. Although tumor cell-derived extracellular vesicles (EVs) promote osteoclast differentiation and bone resorption, their roles in osteoblast differentiation and functions have not been elucidated. In this study, we investigated the effects of breast cancer cell-derived EVs on osteoblast differentiation and functions in vitro. We found that upon osteogenic induction, 4T1 bone metastatic mouse mammary tumor cell-derived EVs (4T1-EVs) were inhibited matrix mineralization of ST2 mouse bone marrow stromal cells. Temporal expression analysis of osteoblast marker genes, including runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), collagen type I (Col1a1), bone sialoprotein (Bsp), and osteocalcin (Bglap) revealed that 4T1-EVs decreased their expression during the late stage of osteoblast differentiation. Elevated levels of c-Jun N-terminal kinase (JNK) phosphorylation, upon osteogenic induction, were diminished by 4T1-EVs, significantly. In contrast, the nullification of reduced JNK phosphorylation by anisomycin, a potent JNK activator, increased the expression levels of osteoblast differentiation markers. Overall, our data indicated that 4T1-EVs affect osteoblast maturation, at least partially, through the regulation of JNK activity, which provides novel insights into the pathological impact of osteolytic bone metastasis and the role of EVs in osteoblast differentiation.
AB - The metastases of breast cancer to bone often cause osteolytic lesions not only by stimulating osteoclasts to resorb the bone but also by inhibiting osteoblasts from bone formation. Although tumor cell-derived extracellular vesicles (EVs) promote osteoclast differentiation and bone resorption, their roles in osteoblast differentiation and functions have not been elucidated. In this study, we investigated the effects of breast cancer cell-derived EVs on osteoblast differentiation and functions in vitro. We found that upon osteogenic induction, 4T1 bone metastatic mouse mammary tumor cell-derived EVs (4T1-EVs) were inhibited matrix mineralization of ST2 mouse bone marrow stromal cells. Temporal expression analysis of osteoblast marker genes, including runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), collagen type I (Col1a1), bone sialoprotein (Bsp), and osteocalcin (Bglap) revealed that 4T1-EVs decreased their expression during the late stage of osteoblast differentiation. Elevated levels of c-Jun N-terminal kinase (JNK) phosphorylation, upon osteogenic induction, were diminished by 4T1-EVs, significantly. In contrast, the nullification of reduced JNK phosphorylation by anisomycin, a potent JNK activator, increased the expression levels of osteoblast differentiation markers. Overall, our data indicated that 4T1-EVs affect osteoblast maturation, at least partially, through the regulation of JNK activity, which provides novel insights into the pathological impact of osteolytic bone metastasis and the role of EVs in osteoblast differentiation.
UR - http://www.scopus.com/inward/record.url?scp=85177214692&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85177214692&partnerID=8YFLogxK
U2 - 10.1016/j.abb.2023.109821
DO - 10.1016/j.abb.2023.109821
M3 - Article
C2 - 37979903
AN - SCOPUS:85177214692
SN - 0003-9861
VL - 750
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
M1 - 109821
ER -
