Linarin and its aglycone acacetin abrogate actin ring formation and focal contact to bone matrix of bone-resorbing osteoclasts through inhibition of αvβ3 integrin and core-linked CD44

Kim, Soo-Il; Kim, Yun‐Ho; Kang, Beom Goo; Kang, Min‐Kyung; Lee, Eunjung; Kim, Dong Yeon; Oh, Hyeongjoo; Oh, Sang‐Ha; Na, Woojin; Lim, Soon Sung; Kang, Young‐Hee

doi:10.1016/j.phymed.2020.153351

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…Recently, studies have shown that a large number of compounds, such as cladrin, icariin, and petunidin have inhibitory effects on osteoclast function and represent potential therapies for bone resorption diseases ( Bellavia et al, 2021 ). Acacetin has been reported to promote osteoblastic differentiation and mineralization ( Li et al, 2016 ) and inhibit osteoclastic differentiation through regulating CD44 and integrins in vitro ( Kim et al, 2020 ). However, the effect and mechanism of acacetin on the formation of osteoclasts and type H vessels in OVX-induced bone loss have not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…It exerts pronounced anti-inflammatory, anti-peroxidative, and anti-cancer activities ( Wang et al, 2020 ). Interestingly, acacetin has been reported to promote osteoblastic differentiation and mineralization ( Li et al, 2016 ) and inhibit osteoclastic differentiation in vitro ( Kim et al, 2020 ). However, the effect of acacetin on the formation of osteoclasts and type H vessels, and its protective function in boss loss in vivo are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Lin

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Osteoporosis, characterized by the destruction of bone resorption and bone formation, is a serious disease that endangers human health. Osteoporosis prevention and treatment has become one of the important research contents in the field of medicine. Acacetin, a natural flavonoid compound, could promote osteoblast differentiation, and inhibit osteoclast formation in vitro. However, the mechanisms of acacetin on osteoclast differentiation and type H vessel formation, as well as the effect of preventing bone loss, remain unclear. Here, we firstly used primary bone marrow derived macrophages (BMMs), endothelial progenitor cells (EPCs), and ovariectomized (OVX) mice to explore the function of acacetin on bone remodeling and H type vessel formation. In this study, we found that acacetin inhibits osteoclast formation and bone resorption of BMMs induced by the macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) in a concentration of 20 μM without exerting cytotoxic effects. It was accompanied by downregulation of osteoclast differentiation marker genes (Ctsk, Acp5, and Mmp9) and cell fusion genes (CD9, CD47, Atp6v0d2, Dc-stamp, and Oc-stamp). Moreover, acacetin disrupted actin ring formation and extracellular acidification in osteoclasts. Mechanistic analysis revealed that acacetin not only inhibits the expression of the major transcription factor NFATc1 and NF-κB during RANKL-induced osteoclast formation, but also suppresses RANKL-induced the phosphorylation of Akt, GSK3β, IκBα, and p65. Additionally, acacetin enhanced the ability of M-CSF and RANKL-stimulated BMMs to promote angiogenesis and migration of EPCs. We further established that, in vivo, acacetin increased trabecular bone mass, decreased the number of osteoclasts, and showed more type H vessels in OVX mice. These data demonstrate that acacetin prevents OVX-induced bone loss in mice through inhibition of osteoclast function and promotion of type H vessel formation via Akt/GSK3β and NF-κB signalling pathway, suggesting that acacetin may be a novel therapeutic agent for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Lin

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…In addition, a reducing impact of LN on the RANKL-induced macrophage differentiation into multinucleated osteoclasts and osteoclastic bone resorption through reducing lacunar acidification and bone matrix degradation has been demonstrated. Moreover, LN reduced the transmigration and focal contact of osteoclasts to bone matrix-mimicking RGD peptide, which was accomplished by inhibiting the induction of integrins, integrinassociated proteins of paxillin, and gelsolin, cdc42, and CD44 involved in the formation of actin rings [88].…”

Section: Anti-osteoporosis Activitymentioning

confidence: 99%

Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review

et al. 2021

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Many flavonoids, as eminent phenolic compounds, have been commercialized and consumed as dietary supplements due to their incredible human health benefits. In the present study, a bioactive flavone glycoside linarin (LN) was designated to comprehensively overview its phytochemical and biological properties. LN has been characterized abundantly in the Cirsium, Micromeria, and Buddleja species belonging to Asteraceae, Lamiaceae, and Scrophulariaceae families, respectively. Biological assessments exhibited promising activities of LN, particularly, the remedial effects on central nervous system (CNS) disorders, whereas the remarkable sleep enhancing and sedative effects as well as AChE (acetylcholinesterase) inhibitory activity were highlighted. Of note, LN has indicated promising anti osteoblast proliferation and differentiation, thus a bone formation effect. Further biological and pharmacological assessments of LN and its optimized semi-synthetic derivatives, specifically its therapeutic characteristics on osteoarthritis and osteoporosis, might lead to uncovering potential drug candidates.

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“…21,22 Through this, the bumps of the cell surface and cytoskeleton including the filopodia and lamellipodia could combine with intracellular proteins, for example, the vinculin, α-actinin, and paxillin to attach to the ECM. 23 Inhibition of integrin ανβ3 suppresses osteoclastogenesis, 24 and on the contrary, it indicated that integrin ανβ3 has positive effects on osteogenesis. 25,26 Titanium with nanotopography induces osteoblast differentiation through regulation of integrin αV, 27,28 and in on our previous study, TiO 2 -NTs were involved in adhesion of the cell on the surface of materials.…”

Section: Introductionmentioning

confidence: 99%

Titania-Nanotube-Coated Titanium Substrates Promote Osteogenesis and Suppress Osteoclastogenesis via Integrin ανβ3

Kang

Dong

Liu

et al. 2022

ACS Appl. Bio Mater.

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The balance of bone turnover mediated by osteoclastogenesis and osteogenesis implants that could suppress osteoclastogenesis and promote osteogenesis is an appropriate treatment strategy for osteoporosis patients. Titanium is one of the most applied materials in implants. In this study, titania nanotubes (Ti-NTs) were produced by anodization at 10, 40, and 60 V. We found that Ti-NTs were nontoxic to bone marrow mesenchymal stem cells (BMSCs). Ti-NTs suppressed osteoclast formation and function in a diameter dependent manner in vitro. Furthermore, Ti-NTs enhanced the activity of osteogenesis, expressions of osteogenesis-related marker genes were increased and β-Catenin pathway was active. Alkaline phosphatase (ALP) activity and matrix mineralization were also promoted in vitro. To explore the possible mechanisms, we performed a series of experiments to indicate the effects of Ti-NTs on cytoskeletal organization and integrin ανβ3 expression of osteoclasts and osteoblasts. The results demonstrated that 90-nm-diameter Ti-NTs could suppress the expression of integrin ανβ3 in osteoclast precursor cells. Interestingly, it revealed an opposite effect on BMSCs. Moreover, 90 nm-diameter Ti-NTs prevented ovariectomy (OVX)-induced bone loss. These findings indicated that Ti-NTs could inhibit osteoclastogenesis and enhance osteogenesis; it was mediated via regulation of integrin ανβ3�90 nm-diameter Ti-NT revealed a good biological ability especially suited for osteoporosis treatment.

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Linarin and its aglycone acacetin abrogate actin ring formation and focal contact to bone matrix of bone-resorbing osteoclasts through inhibition of αvβ3 integrin and core-linked CD44

Cited by 14 publications

References 57 publications

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review

Titania-Nanotube-Coated Titanium Substrates Promote Osteogenesis and Suppress Osteoclastogenesis via Integrin ανβ3

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