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We previously found <jats:italic>Penk1<\/jats:italic> to be the most downregulated gene in a whole gene profiling analysis performed in osteoblasts subjected to microgravity as a model of mechanical unloading. In this work, <jats:italic>Penk1<\/jats:italic> downregulation was confirmed in the bones of two in vivo models of mechanical unloading: tail-suspended and botulinum toxin A (botox)-injected mice. Consistently, in the sera from healthy volunteers subjected to bed rest, we observed an inverse correlation between PENK1 and bed rest duration. These results prompted us to investigate a role for this factor in bone. <jats:italic>Penk1<\/jats:italic> was highly expressed in mouse bone, but its global deletion failed to impact bone metabolism in vivo. Indeed, <jats:italic>Penk1<\/jats:italic> knock out (<jats:italic>Penk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) mice did not show an overt bone phenotype compared to the WT littermates. Conversely, in vitro<jats:italic> Penk1<\/jats:italic> gene expression progressively increased during osteoblast differentiation and its transient silencing in mature osteoblasts by siRNAs upregulated the transcription of the <jats:italic>Sost1<\/jats:italic> gene encoding sclerostin, and decreased <jats:italic>Wnt3a<\/jats:italic> and <jats:italic>Col1a1<\/jats:italic> mRNAs, suggesting an altered osteoblast activity due to an impairment of the Wnt pathway<jats:italic>.<\/jats:italic> In line with this, osteoblasts treated with the <jats:italic>Penk1<\/jats:italic> encoded peptide, Met-enkephalin, showed an increase of <jats:italic>Osx<\/jats:italic> and <jats:italic>Col1a1<\/jats:italic> mRNAs and enhanced nodule mineralization. Interestingly, primary osteoblasts isolated from <jats:italic>Penk1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice showed lower metabolic activity, ALP activity, and nodule mineralization, as well as a lower number of CFU-F compared to osteoblasts isolated from WT mice, suggesting that, unlike the transient inhibition, the chronic <jats:italic>Penk1<\/jats:italic> deletion affects both osteoblast differentiation and activity. Taken together, these results highlight a role for Penk1 in the regulation of the response of the bone to mechanical unloading, potentially acting on osteoblast differentiation and activity in a cell-autonomous manner.<\/jats:p>","DOI":"10.1007\/s00223-024-01199-z","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T09:48:33Z","timestamp":1710928113000},"page":"524-534","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pre-proenkephalin 1 is Downregulated Under Unloading and is Involved in Osteoblast Biology"],"prefix":"10.1007","volume":"114","author":[{"given":"Chiara","family":"Puri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Dannenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argia","family":"Ucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ponzetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Pucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Silvestri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Frings-Meuthen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Heer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Rucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Teti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Maurizi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"issue":"1","key":"1199_CR1","first-page":"1","volume":"23","author":"X Wang","year":"2020","unstructured":"Wang X, Xu J, Kang Q (2020) Neuromodulation of bone: role of different peptides and their interactions (review). 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The study is registered on  with the unique trial number: NCT01183299; registration date: August 13, 2010. The animal study was approved by the Italian Ministry of Health. Approval N. 392\/2020-PR.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}]}}