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CTLA\u20104 also binds to the surfaces of monocytes and macrophages, precursors of osteoclasts. Research on rheumatoid arthritis demonstrated that CTLA\u20104\u00a0suppresses inflammation and bone resorption. However, its effects on alveolar bone have yet to be understood. The purpose of this study was to investigate the role and potential mechanism of CTLA\u20104 in bone resorption in periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>In vivo, the effects of systemic administration of CTLA\u20104 immunoglobulin fusion protein (CTLA\u20104\u2010Ig) on alveolar bone resorption were investigated using a periodontitis mouse model. A total of 20 C57BL\/6J mice were randomly assigned to two groups according to the administration modes. Periodontitis was induced by placing a ligature around the left maxillary second molar. The contralateral tooth was left un\u2010ligated. In the CTLA\u20104\u2010Ig (+) group, CTLA\u20104\u2010Ig was administered by intraperitoneal injection at 1 and 3\u00a0days after ligature placement. Animals in the CTLA\u20104\u2010Ig (\u2212) group were given only phosphate\u2010buffered saline each time. At 5\u00a0days after ligature placement, bone resorption was assessed by micro\u2010computed tomography and histological examination, and the prevalence of osteoclast\u2010like cells was assessed by tartrate\u2010resistant acid phosphatase (TRAP) staining. In vitro, the effects of CTLA\u20104\u2010Ig on osteoclasts were evaluated. Viability of RAW 264.7 cells treated with receptor activator of nuclear factor\u2010\u03baB ligand (RANKL) and CTLA\u20104\u2010Ig was tested by WST\u20101 assay. Osteoclast\u2010like cells were enumerated by TRAP staining, and osteoclast activity was evaluated by resorption pit assay. Gene expression levels of osteoclast differentiation markers (macrophage\u2010colony stimulating factor receptor, carbonic anhydrase II, cathepsin K, and Trap) and protein phosphatase 2A (PP2A), a major serine\u2010threonine phosphatase, were assessed by quantitative real\u2010time polymerase chain reaction. The effect of CTLA\u20104\u2010Ig on the nuclear factor\u2010\u03baB (NF\u2010\u03baB) activation was assessed by enzyme\u2010linked immunosorbent assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vivo, ligature\u2010induced bone resorption and the numbers of osteoclast\u2010like cells were significantly decreased by the administration of CTLA\u20104\u2010Ig. In vitro, treatment with RANKL and CTLA\u20104\u2010Ig had no significant effect on cell viability. CTLA\u20104\u2010Ig significantly reduced the prevalence and activation of osteoclast\u2010like cells and decreased the expressions of osteoclast differentiation markers, compared with the RANKL\u2010treated control. CTLA\u20104\u2010Ig significantly suppressed RANKL\u2010induced phosphorylation of NF\u2010\u03baB p65 but increased PP2A expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results suggest that CTLA\u20104\u2010Ig abrogates bone resorption in induced periodontitis, possibly via inhibition of osteoclast differentiation and activation. The regulation of the NF\u2010\u03baB pathway and PP2A expression may be one mechanism by which CTLA\u20104\u2010Ig suppresses osteoclast behavior.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12909","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T12:45:51Z","timestamp":1623761151000},"page":"972-981","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Systemic administration of cytotoxic T lymphocyte\u2010associated antigen 4 (CTLA\u20104)\u2010Ig abrogates alveolar bone resorption in induced periodontitis through inhibition of osteoclast differentiation and activation: An experimental investigation"],"prefix":"10.1111","volume":"56","author":[{"given":"Saki","family":"Nakane","sequence":"first","affiliation":[{"name":"Department of Periodontology Tokyo Dental College Tokyo Japan"},{"name":"Oral Health Science Center Tokyo Dental College Tokyo 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