2018
DOI: 10.1371/journal.pbio.2002979
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A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy

Abstract: There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and αvβ3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulat… Show more

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Cited by 25 publications
(27 citation statements)
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“…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%
“…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%
“…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%
“…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%