A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy

Zur, Yuval; Rosenfeld, Lior; Keshelman, Chen Anna; Dalal, Nofar; Guterman-Ram, Gali; Orenbuch, Ayelet; Einav, Yulia; Levaot, Noam; Papo, Niv

doi:10.1371/journal.pbio.2002979

Cited by 23 publications

(27 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Their differentiation and activity are regulated by a variety of hormones and cytokines, including MCSF and RANKL: these two cytokines are critical for the regulation of OC-like cell differentiation in vitro [20]. Therefore, we selected both MCSF and RANKL to induce THP-1 cells into OCs and showed that they were functionally able to induce OC differentiation, which is a finding consistent with that of a previous study [21]. The anti-bone resorption effects of AL are mainly achieved via the inhibition of OCs.…”

Section: Discussionsupporting

confidence: 87%

Circular RNA atlas in osteoclast differentiation with and without alendronate treatment

Lin

Zhu

et al. 2020

J Orthop Surg Res

View full text Add to dashboard Cite

Background: Alendronate (AL) is the most widely used bisphosphonate in the treatment of osteoporosis (OP). However, the role of circular RNAs (circRNAs) in the treatment of OP with AL remains unclear. Methods: In this study, we showed that osteoclast (OC) precursors (OPCSs) could be induced into OCs with macrophage colony-stimulating factor (MCSF) and receptor activator of nuclear factor-κB ligand (RANKL) treatment. Subsequently, the OCs were treated with AL. OC differentiation-related biomarkers including RANK, tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were analyzed with TRAP staining, quantitative real-time (qPCR), and western blotting. Differentially expressed circRNAs (DECs) were identified among the OPCS, OC, and OC + AL groups. In addition, the expression levels of 10 DECs related to OC differentiation were verified by qPCR. Results: TRAP staining showed that MCSF and RANKL treatment effectively induced OPCSs to differentiate into OCs. In addition, qPCR and western blot analysis revealed that the three biomarkers of OC (RANK, TRAP, and CTSK) were expressed significantly more in the OC group than those in the OPCS group. In contrast, the mRNA and protein expression levels of these three biomarkers decreased significantly in OCs treated with AL compared with those non-treated OCs. GO analysis of the DECs in the OPCS group vs. the OC group revealed that their functions were mainly related to cell, cell part, binding, and single-organism terms. KEGG analysis of the top 20 DECs in a comparison between the OPCS and OC groups showed that genes involved in mitogen-activated protein kinase signaling were the most common. Results of functional analyses of DECs in an OC vs. OC + AL comparison were similar to those in the OPCS vs. OC comparison. Finally, qPCR showed that, in the OC + AL vs. OC group comparison, the expression levels of seven and three DECs significantly decreased and increased, respectively. Conclusions: Having successfully induced OPCSs to differentiate into OCs, we showed that AL suppresses the differentiation of OPCS into OC and that 10 DECs were involved in the regulation of this process. This indicates that these DECs might be important to the treatment of OP.

show abstract

Section: Discussionsupporting

confidence: 87%

Circular RNA atlas in osteoclast differentiation with and without alendronate treatment

Lin

Zhu

et al. 2020

J Orthop Surg Res

View full text Add to dashboard Cite

show abstract

“…Therefore, osteoclasts remain the primary cellular target for the identification and development of therapeutic agents that are effective in the treatment of osteoporosis. Currently, the therapeutic agents used clinically to treat osteoporosis are selective estrogen receptor modulators (SERMs), Denosumab (anti-RANKL antibody), bisphosphonates, parathyroid hormone, and health supplements including calcium and vitamin D (Cranney et al, 2002;Zur et al, 2018). However, side effects such as nephrotoxicity, osteonecrosis, endometrial cancer risk, and jaw bone necrosis limit the use of these agents (Khan et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Vindoline Inhibits RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss in Mice

et al. 2020

View full text Add to dashboard Cite

Osteolytic bone diseases, for example postmenopausal osteoporosis, arise from the imbalances between osteoclasts and osteoblasts in the bone remodeling process, whereby osteoclastic bone resorption greatly exceeds osteoblastic bone formation resulting in severe bone loss and deterioration in bone structure and microarchitecture. Therefore, the identification of agents that can inhibit osteoclast formation and/or function for the treatment of osteolytic bone disease has been the focus of bone and orthopedic research. Vindoline (Vin), an indole alkaloid extracted from the medicinal plant Catharanthus roseus, has been shown to possess extensive biological and pharmacological benefits, but its effects on bone metabolism remains to be documented. Our study demonstrated for the first time, that Vin could inhibit osteoclast differentiation from bone marrow macrophages (BMMs) precursor cells as well as mature osteoclastic bone resorption. We further determined that the underlying molecular mechanism of action of Vin is in part due to its inhibitory effect against the activation of MAPK including p38, JNK, and ERK and intracellular reactive oxygen species (ROS) production. This effect ultimately suppressed the induction of c-Fos and NFATc1, which consequently downregulated the expression of the genes required for osteoclast formation and bone resorption. Consistent with our in vitro findings, in vivo administration of Vin protected mice against ovariectomy (OVX)-induced bone loss and trabecular bone deterioration. These results provided promising evidence for the potential therapeutic application of Vin as a novel treatment option against osteolytic diseases.

show abstract

“…GW2580 selectively inhibits the tyrosine kinase domain of CSF-1R 25 and is shown to be effective in targeting tumour invasion when used in isolation, and potentiates its efficacy when used in combination with indoximod therapy 26 . Recently, engineered bi-specific inhibitors have been developed that simultaneously target the unique combination of CSF-1 and integrins 27 , these dual-specific proteins could bind to and inhibit both CSF-1 and αvβ3 integrin and have shown superior therapeutic potential, as compared to monospecific protein therapeutics. Our recent published work has pointed a role of endometrial receptivity marker and cell adhesion protein, integrin β1 (ITGB1), in the embryo attachment within FT, as a result of past chlamydial infection 28 .…”

Section: Discussionmentioning

confidence: 99%

Targeting colony stimulating factor-1 receptor signalling to treat ectopic pregnancy

Ahmad

Duncan

Campbell

et al. 2020

Sci Rep

View full text Add to dashboard Cite

1–2% of pregnancies are ectopic, the majority implanting in the Fallopian tube. A single, systemic dose of methotrexate, a DNA-synthesis (S phase) inhibitor, has been used since 1991 for outpatient treatment of women with stable EP. However, methotrexate has limited clinical and cost effectiveness, restricting its use to 25–30% of these women. There is an unmet need for better medical treatment for EP. Colony stimulating factor-1 (CSF-1) promotes placentation and creates a pro-inflammatory environment that is fundamental for the maintenance of a normal pregnancy. We hypothesised that CSF-1 is also involved in the placentation and maintenance of an EP. Herein, we demonstrate the immunolocalisation of the CSF-1 receptor (CSF-1R) as well as its ligand (CSF-1) in immortalised first trimester trophoblast cells. We show that a specific CSF-1R kinase inhibitor, GW2580, abolishes CSF-1 induced trophoblast cell proliferation and migration and can be cytotoxic. We then demonstrate the expression of CSF-1R and CSF-1 in the cytotrophoblast and syncytiotrophoblast within ectopic implantation sites from women with EP. Our data suggests that CSF-1 is involved in the survival and proliferation of trophoblast cells in EP. This suggests that pharmacological disruption of CSF-1/CSF-1R signaling axis could be the basis of a new therapeutic for EP.

show abstract

A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy

Cited by 23 publications

References 43 publications

Circular RNA atlas in osteoclast differentiation with and without alendronate treatment

Circular RNA atlas in osteoclast differentiation with and without alendronate treatment

Vindoline Inhibits RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss in Mice

Targeting colony stimulating factor-1 receptor signalling to treat ectopic pregnancy

Contact Info

Product

Resources

About