Inhibition of osteoporosis by the αvβ3 integrin antagonist of rhodostomin variants

Lin, Tao; Yang, Rong‐Sen; Tu, Huang Ju; Liou, Houng Chi; Lin, Y.; Chuang, Woie Jer; Fu, Wen

doi:10.1016/j.ejphar.2017.03.019

Cited by 19 publications

(11 citation statements)

References 17 publications

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“…Expression of NFATc1 is dependent on TNF receptorassociated factor 6 (TRAF6) and downstream cascades such as NF-κB, MAPK, and calcium-signaling pathways (Kim & Kim, 2014). In turn, NFATc1 regulates the expression of target genes that enable osteoclast attachment to the bone and mediate their bone resorptive functions (Cui et al, 2017;Dharmapatni et al, 2017;Lin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

Guo

Cao

Wu³

et al. 2018

Journal Cellular Physiology

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Osteoclasts are responsible for bone resorption during the process of bone remodeling. Increased osteoclast numbers and bone resorption activity are the main factors contributing to bone loss-related diseases such as osteoporosis. Therefore, modulating the formation and function of osteoclasts is critical for the effective treatment of osteolysis and osteoporosis. Kavain is the active ingredient extracted from the root of the kava plant, which possesses known anti-inflammatory properties. However, the effects of kavain on osteoclastogenesis and bone resorption remain unclear. In this study, we found that kavain inhibits receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and fusion using tartrate-resistant acid phosphatase staining and immunofluorescence. Furthermore, kavain inhibited bone resorption performed by osteoclasts. Using reverse transcription-polymerase chain reaction and western blot analysis, we found that kavain downregulates the expression of osteoclast marker genes, such as nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), v-atpase d2 (Atp6v0d2), dendrocyte expressed seven transmembrane protein (Dcstamp), matrix metallopeptidase 9 (Mmp9), cathepsin K (Ctsk), and Acp5. Additionally, kavain repressed RANKL-induced calcium oscillations, nuclear factor of activated T cells activation, and mitogen-activated protein kinase phosphorylation, while leaving NF-κB unaffected. We found no effects of kavain on either osteoblast proliferation or differentiation. Besides, kavain inhibited bone loss in ovariectomized mice by suppressing osteoclastogenesis. Collectively, these data suggest a potential use for kavain as a candidate drug for the treatment of osteolytic diseases.

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Section: Discussionmentioning

confidence: 99%

Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

Guo

Cao

Wu³

et al. 2018

Journal Cellular Physiology

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“…In recent years, biologic drugs such as TNF inhibitors, integrin receptor antagonists or IL-23 antagonist have gained importance in the treatment of IBD patients [29]. Besides, their potential role in osteoporosis treatment has been proven as well [30,31,32]. Nevertheless, despite high effectiveness, they can have severe side-effects, like infections due to immunosuppression or malignancies.…”

Section: Introductionmentioning

confidence: 99%

ESR1 Gene Variants Are Predictive of Osteoporosis in Female Patients with Crohn’s Disease

Krela‐Kaźmierczak

Skrzypczak-Zielińska

Kaczmarek-Ryś

et al. 2019

JCM

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Decreased bone mass in patients with inflammatory bowel diseases (IBD) is a clinical problem with extremely severe consequences of osteoporotic fractures. Despite its increasing prevalence and the need for mandatory intervention and monitoring, it is often ignored in IBD patients’ care. Determining the biomarkers of susceptibility to bone mineral density disorder in IBD patients appears to be indispensable. We aim to investigate the impact of estrogen receptor gene (ESR1) gene polymorphisms on bone mineral density (BMD) in patients with ulcerative colitis (UC) and Crohn’s disease (CD), as they may contribute both, to osteoporosis and inflammatory processes. We characterised 197 patients with IBD (97 with UC, 100 with CD), and 41 controls carrying out vitamin D, calcium and phosphorus serum levels, and bone mineral density assessment at the lumbar spine and the femoral neck by dual-energy X-ray absorptiometry (DXA), ESR1 genotyping and haplotype analysis. We observed that women with CD showed the lowest bone density parameters, which corresponded to the ESR1 c.454-397T and c.454-351A allele dose. The ESR1 gene PvuII and XbaI TA (px) haplotype correlated with decreased femoral neck T-score (OR = 2.75, CI = [1.21–6.27], P-value = 0.016) and may be predictive of osteoporosis in female patients with CD.

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“…As integrin α v β 3 mediates the attachment of OCs onto bone matrix proteins, it is reasonable to hypothesize that inhibiting the subunit of this integrin may prevent bone resorption. In different animal models of induced osteoporosis, α v β 3 integrin antagonists such as L-000845704 and HSA-ARLDDL significantly increase the BMD (Murphy et al, 2005;Lin et al, 2017). In addition, a dual-specific protein, macrophage colony-stimulating factor (M-CSF RGD ), may bind to and inhibit both c-FMS and α v β 3 integrin.…”

Section: Anti-resorptive Drugs Under Development Targeting the Molecules Of Resorption Lacunamentioning

confidence: 99%

“…(Lindström et al, 2018) The RCT trails were conducted only in osteoarthritis currently (Conaghan et al, 2020) α v β 3 integrin antagonist L-000845704 Significant increase in spinal BMD. (Murphy et al, 2005) Only several preclinical studies in vitro and animal study HSA-ARLDDL Prevention of ovariectomized-induced reduction in cancellous bone volume, bone surface, and trabecular number in rats (Lin et al, 2017) M-CSF RGD i) A dual-specific protein able to bind to and inhibit both c-FMS and α v β 3 integrin ii) Suppressing osteoclast activity (Zur et al, 2018) Chloride channel-7 inhibitor N53736 i) Overcoming the defect in bone degradation due to the inability to acidify the sealing zone ii) A long-term anti-resorptive effect in ovariectomized rats (Schaller et al, 2004) No clinical trials Wieschaus, 2004;MacDonald et al, 2009;Baron and Kneissel, 2013) (Figure 2). Non-canonical Wnt signaling pathway is independent of β-catenin, instead, it takes effects by activating the heterotrimeric G-proteins and protein kinase C (PKC), which inhibits MSC differentiation toward adipocyte lineage and stimulates the nuclear factor of activated T cells (NFAT) to regulate bone formation and bone resorption (Kohn and Moon, 2005).…”

Section: Miv-711mentioning

confidence: 99%

Recent Progresses in the Treatment of Osteoporosis

Xie

et al. 2021

Front. Pharmacol.

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Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.

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Inhibition of osteoporosis by the αvβ3 integrin antagonist of rhodostomin variants

Cited by 19 publications

References 17 publications

Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

ESR1 Gene Variants Are Predictive of Osteoporosis in Female Patients with Crohn’s Disease

Recent Progresses in the Treatment of Osteoporosis

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