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This confirms the bone as a target tissue for per- and polyfluoroalkyl substances (PFAS). However, it is still unclear during which phase, proliferation or differentiation, PFOA exerts the most significant harm on osteoblasts, the cells responsible for secreting bone matrix. To tackle the intriguing question of how PFOA treatment affects the process, this study investigated the impact of different concentrations of PFOA on 2D and 3D human fetal osteoblast (hFOB1.19) cell line cultures representing the proliferation and differentiation phases, respectively. In 2D cultures, a 6-day PFOA exposure impaired antioxidant defense without directly altering osteogenesis or calcium deposition. In 3D spheroids, PFOA disrupted spheroid morphology and the deposition of the organic component of extracellular matrix (ECM) in a time-dependent manner. Given the relevance of the endocannabinoid system (ECS) in bone remodeling, we further assessed cannabinoid receptor 1 (CB1) levels. In 2D cultures, 10\u2009\u00b5M PFOA reduced CB1 protein levels in parallel with decreased collagen levels. Conversely, in 3D spheroids, exposure to 100\u2009\u00b5M PFOA for 2 days significantly increased CB1 levels while reducing the levels of degraded collagen. These findings emphasize the non-monotonic, phase- and time-dependent effects of PFOA on osteoblast function and ECM deposition, underscoring the need for further research into its long-term impact on bone homeostasis and human health induced by this emerging concern contaminant.<\/jats:p>","DOI":"10.1038\/s41420-025-02863-5","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:43:01Z","timestamp":1767969781000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unveiling the toxic effects of perfluorooctanoic acid on osteoblast function and extracellular matrix deposition using 2D and 3D models"],"prefix":"10.1038","volume":"12","author":[{"given":"Fiorenza","family":"Sella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0018-8096","authenticated-orcid":false,"given":"Caterina","family":"Licini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2042-798X","authenticated-orcid":false,"given":"Marta","family":"Lomb\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Giommi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Carbonari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-2776","authenticated-orcid":false,"given":"Monica","family":"Mattioli-Belmonte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-0572","authenticated-orcid":false,"given":"Oliana","family":"Carnevali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"2863_CR1","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1016\/j.bpj.2020.06.026","volume":"119","author":"X Chen","year":"2020","unstructured":"Chen X, Hughes R, Mullin N, Hawkins RJ, Holen I, Brown NJ, et al. 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