{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:59:58Z","timestamp":1792803598715,"version":"4.5.0"},"reference-count":194,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Harrington Cancer and Health Foundation"},{"name":"Brain Drug Discovery Center, Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center","id":[{"id":"https:\/\/ror.org\/033ztpr93","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The bone and brain, though distinct in structure and function, share remarkable physical, molecular, and developmental similarities. Emerging evidence reveals dynamic bidirectional crosstalk between these systems mediated by hormones, cytokines, extracellular vesicles (EVs), and neural signals. Bone-derived factors such as osteocalcin (OCN), lipocalin-2, and fibroblast growth factor (FGF) 23 influence cognitive functions, mood, and neurogenesis, while brain- and nerve-derived mediators, including leptin, serotonin, and sympathetic signals, modulate bone remodeling. Inflammation and aging disrupt this communication, contributing to cognitive decline, osteoporosis, and other age-related disorders. Stem cells and EVs have also been implicated as mediators in this axis, offering insights into regenerative strategies. Molecular signaling pathways and transcriptional regulators, such as Wnt\/\u03b2-catenin, leptin, receptor activator of nuclear factor kappa-B ligand (RANKL), sclerostin (SOST), and nuclear factor kappa-B (NF-\u03baB), play critical roles in maintaining bone\u2013brain homeostasis. Additionally, shared biomarkers and pathological links between neurodegeneration and bone loss suggest new diagnostic and therapeutic opportunities. Studies support this inter-organ communication, yet further mechanistic and translational research is needed. This review highlights the molecular basis of bone\u2013brain crosstalk, emphasizing inflammation, aging, and regulatory pathways, with a focus on future directions in biomarker discovery and therapeutic targeting. Understanding this crosstalk may help in early diagnosis and dual-targeted interventions for both bone and brain disorders.<\/jats:p>","DOI":"10.3390\/biology14091279","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T08:03:47Z","timestamp":1758096227000},"page":"1279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unraveling the Bone\u2013Brain Communication Network"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4773-3629","authenticated-orcid":false,"given":"Surajit","family":"Hansda","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. 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Hodge School of Pharmacy, Texas Tech University Health Sciences Center, ARB Suite 2116, 1406 South Coulter Street, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature10763","article-title":"The contribution of bone to whole-organism physiology","volume":"481","author":"Karsenty","year":"2012","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.cell.2007.05.047","article-title":"Endocrine regulation of energy metabolism by the skeleton","volume":"130","author":"Lee","year":"2007","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0092-8674(02)01049-8","article-title":"Leptin regulates bone formation via the sympathetic nervous system","volume":"111","author":"Takeda","year":"2002","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0092-8674(00)81558-5","article-title":"Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass","volume":"100","author":"Ducy","year":"2000","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.cell.2013.08.042","article-title":"Maternal and offspring pools of osteocalcin influence brain development and functions","volume":"155","author":"Oury","year":"2013","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.cell.2011.02.004","article-title":"Endocrine regulation of male fertility by the skeleton","volume":"144","author":"Oury","year":"2011","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1111\/j.1365-2362.2011.02545.x","article-title":"Effects of inflammatory and anti-inflammatory cytokines on the bone","volume":"41","author":"Schett","year":"2011","journal-title":"Eur. 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