{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:29:07Z","timestamp":1786361347362,"version":"build-2736575974"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteoporosis is a prevalent metabolic bone disorder driven by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and current pharmacological options remain limited by adverse effects and incomplete mechanistic targeting. Copper, an essential trace element, has long been linked to bone mineral density through population-level dietary surveys, but whether and how copper mechanistically shapes osteoblast and osteoclast function at the subcellular level has not been systematically reviewed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We synthesised genetic, clinical, and cell-biological evidence\u2014including copper-transporter mutation models (Menkes and Wilson disease), organelle-specific trafficking studies, and mechanistic work on copper-dependent enzymes and chaperones\u2014to construct an organelle-resolved account of copper handling in bone cells, extending beyond the mitochondria and trans-Golgi network to include the endoplasmic reticulum and the lysosomal\/endosomal system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Copper regulates bone metabolism through distinct, organelle-specific, and cell-type-specific mechanisms. In mitochondria, physiological copper supports oxidative phosphorylation and osteogenesis, whereas copper overload can trigger cuproptosis, a mechanistically distinct form of cell death mediated by FDX1-dependent aggregation of lipoylated tricarboxylic acid cycle proteins; whether this pathway selectively affects osteoclasts remains an open, and in part contested, question, since the hypoxic bone marrow niche may confer glycolysis-associated protection. In the trans-Golgi network, ATP7A\/ATP7B-dependent maturation of lysyl oxidase supports collagen cross-linking, while COMMD1 restrains NF-\u03baB-driven osteoclastogenesis. Emerging evidence implicates copper-dependent PERK activity in endoplasmic reticulum proteostasis relevant to osteoblast secretory function, and lysosomal CTR2-mediated copper release as a candidate regulator of mTORC1-autophagy signalling in osteoclasts, although direct evidence in bone cells for both pathways is still lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Copper acts as a compartment-specific and cell-type-specific regulator of bone remodelling rather than a uniform, dose-dependent factor. Trans-Golgi-network-targeted strategies to enhance lysyl oxidase maturation are the most mechanistically mature translational direction, whereas mitochondria- and lysosome-targeted approaches remain hypothesis-generating and require direct validation in osteoblasts and osteoclasts before therapeutic development can reasonably proceed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1880910","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:42:52Z","timestamp":1786358572000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Copper homeostasis and organelle-dependent mechanisms in bone metabolism: implications for osteoporosis therapy"],"prefix":"10.3389","volume":"14","author":[{"given":"Jialun","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengju","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Zhejiang Chinese Medical University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1111\/iej.12796","article-title":"Lysyl oxidase-mediated VEGF-induced differentiation and angiogenesis in human dental pulp cells","volume":"51","author":"Bae","year":"2018","journal-title":"Int. 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