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Disruption of this balance marks the onset of various bone disorders, such as osteoporosis. In our previous study, we demonstrated that non-coding RNAs (ncRNAs) were able to regulate OC behaviour. Specifically, the long ncRNA <jats:italic>DLEU1<\/jats:italic> and the small ncRNA miR-16 independently control OCs multinuclearity, fusion and resorption. Herein, we investigate whether OCs modulated with ncRNAs impact the behaviour of osteoblast lineage cells (OBs) in a biomimetic co-culture system. Communication between OB and OC comprises numerous molecules and processes, including the secretion of coupling factors, release of matrix-derived signals during bone resorption, and exposure of previously occluded proteins within the bone resorption cavities. Firstly, we explored how ncRNAs influence the composition of the secretome and the remodelling of resorption cavities left by the ncRNA-engineered-OCs on OBs responses. In our OC\/OB co-culture system, conducted in the absence of FBS and exogenous RANKL, we observed changes in the levels of secreted factors 72\u00a0h after <jats:italic>DLEU1<\/jats:italic> levels were decreased in mature OCs (siDLEU1-OC condition), specifically in RANKL, leptin, osteocalcin, MMP7, MMP8, TIMP1 and TIMP2. Meanwhile, leptin and MMP8 levels were increased in the OC\/OB co-culture when miR-16 was overexpressed in OCs (miR-16-OC condition). The results also show that OBs co-cultured with siDLEU1-OCs exhibited impaired migratory capacity and increased ALP levels, while OBs co-cultured with miR-16-OCs displayed a tendency towards decreased elongation. On bone slices, OBs persisted for a longer duration in the trenches created by siDLEU1-OCs. Besides altering OBs behaviour, silencing of <jats:italic>DLEU1<\/jats:italic> reduced the area of each individual trench cavity, while miR-16 overexpression significantly hindered the total eroded surface and inhibited trench formation in the OC\/OB co-culture system. Overall, these findings identify <jats:italic>DLEU1<\/jats:italic> and miR-16 as key regulators in the interplay between human primary OBs and OCs, highlighting the potential of targeting ncRNAs in OCs to modulate their paracrine and matrix-mediated effects on OBs.<\/jats:p>","DOI":"10.1186\/s12964-025-02324-7","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T06:12:29Z","timestamp":1754979149000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Non-coding RNA modulation in osteoclasts and its implications for osteoblast lineage cell behavior in a co-culture system"],"prefix":"10.1186","volume":"23","author":[{"given":"Sara Reis","family":"Moura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob Bastholm","family":"Olesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lindberg-Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rio Adolfo","family":"Barbosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent","family":"S\u00f8e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria In\u00eas","family":"Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"2324_CR1","doi-asserted-by":"publisher","first-page":"25103","DOI":"10.1074\/jbc.R109.041087","volume":"285","author":"LJ Raggatt","year":"2010","unstructured":"Raggatt LJ, Partridge NC. 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