{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:18:38Z","timestamp":1769548718201,"version":"3.49.0"},"reference-count":72,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T00:00:00Z","timestamp":1750982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82102547"],"award-info":[{"award-number":["82102547"]}]},{"name":"National Natural Science Foundation of China","award":["20181113"],"award-info":[{"award-number":["20181113"]}]},{"name":"National Natural Science Foundation of China","award":["2024KTM021"],"award-info":[{"award-number":["2024KTM021"]}]},{"name":"National Natural Science Foundation of China","award":["ZWB2023001"],"award-info":[{"award-number":["ZWB2023001"]}]},{"name":"Natural Science Foundation of Jiangsu Province","award":["82102547"],"award-info":[{"award-number":["82102547"]}]},{"name":"Natural Science Foundation of Jiangsu Province","award":["20181113"],"award-info":[{"award-number":["20181113"]}]},{"name":"Natural Science Foundation of Jiangsu Province","award":["2024KTM021"],"award-info":[{"award-number":["2024KTM021"]}]},{"name":"Natural Science Foundation of Jiangsu Province","award":["ZWB2023001"],"award-info":[{"award-number":["ZWB2023001"]}]},{"name":"Key Grant Project of Chinese Medicine Education Association","award":["82102547"],"award-info":[{"award-number":["82102547"]}]},{"name":"Key Grant Project of Chinese Medicine Education Association","award":["20181113"],"award-info":[{"award-number":["20181113"]}]},{"name":"Key Grant Project of Chinese Medicine Education Association","award":["2024KTM021"],"award-info":[{"award-number":["2024KTM021"]}]},{"name":"Key Grant Project of Chinese Medicine Education Association","award":["ZWB2023001"],"award-info":[{"award-number":["ZWB2023001"]}]},{"name":"Research Project of National Association of Health Industry and Enterprise Management","award":["82102547"],"award-info":[{"award-number":["82102547"]}]},{"name":"Research Project of National Association of Health Industry and Enterprise Management","award":["20181113"],"award-info":[{"award-number":["20181113"]}]},{"name":"Research Project of National Association of Health Industry and Enterprise Management","award":["2024KTM021"],"award-info":[{"award-number":["2024KTM021"]}]},{"name":"Research Project of National Association of Health Industry and Enterprise Management","award":["ZWB2023001"],"award-info":[{"award-number":["ZWB2023001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Macrophage apoptosis, along with inflammation in the interface membrane, has been demonstrated to be significant in the pathogenesis and development of particle-induced periprosthetic osteolysis and aseptic loosening. Additionally, the apoptosis of macrophages is considered an indicator of the resolution phase of inflammation and the transition to normal tissue healing. Therefore, targeting macrophages presents a promising strategy for both the prevention and therapeutic management of periprosthetic osteolysis. In this study, we explored the therapeutic potential of chemical chaperone 4-phenylbutyrate (4-PBA) as a pharmacological intervention aimed at modulating macrophage behaviors, particularly focusing on the processes of apoptosis, inflammation, and osteoclastogenesis in a murine model of TiAl6V4 nanoparticle (TiNP)-induced osteolysis. The results derived from in vivo studies conducted on the murine model provide compelling evidence that TiNPs could trigger osteolysis, activate inflammatory cell infiltration, and promote the differentiation of osteoclasts, accompanied by a notable rise in apoptosis at the osteolytic interface periosteum. The severity of TiNP-induced osteolysis, chaotic bone morphology, extensive bone erosion and destruction, occurrence of infiltrating inflammatory cells, and quantity of osteoclasts were attenuated following co-intervention with 4-PBA. Furthermore, the levels of apoptosis, in conjunction with apoptosis-regulated proteins Bcl-2 and Bax, were accentuated following 4-PBA co-intervention, indicating that the TiNP-induced osteolytic interface periosteum environment exhibited a greater propensity for apoptosis due to the pharmacological intervention of 4-PBA. Notably, the use of 4-PBA as a standalone treatment demonstrated comparatively low levels of toxicity and was deemed to be experimentally safe in mice. These findings indicated that 4-PBA may ameliorate the severity of particle-induced osteolysis by inhibiting the inflammatory response and promoting macrophage apoptosis in a manner that may be beneficial for therapeutic strategies. Thus, pharmacological intervention with 4-PBA appears to be a viable option for addressing osteolysis and aseptic loosening resulting from exposure to wear particles, combining efficacy in promoting apoptosis with a favorable safety profile.<\/jats:p>","DOI":"10.3390\/bioengineering12070701","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T07:42:06Z","timestamp":1751355726000},"page":"701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacological Intervention with 4-Phenylbutyrate Ameliorates TiAl6V4 Nanoparticles-Induced Inflammatory Osteolysis by Promoting Macrophage Apoptosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5570-4564","authenticated-orcid":false,"given":"Guoyin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China"},{"name":"Department of Orthopedics, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianting","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yahui","family":"Fu","sequence":"additional","affiliation":[{"name":"Medical School, Nanjing University, Nanjing 210001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Central Military Commission Joint Logistics Support Force 904th Hospital, Wuxi 214044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Nanjing Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210022, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianning","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Nanjing Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210022, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianmin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2433962","DOI":"10.1001\/jamanetworkopen.2024.33962","article-title":"Outcomes by Race and Ethnicity Following a Medicare Bundled Payment Program for Joint Replacement","volume":"7","author":"Kim","year":"2024","journal-title":"JAMA Netw. 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