{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:07:50Z","timestamp":1784282870342,"version":"3.55.0"},"reference-count":237,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor\u2013bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including \u201cproteoglycans,\u201d \u201cglycosaminoglycans,\u201d \u201cheparan sulfate proteoglycans,\u201d \u201chyaluronan,\u201d \u201cheparanase,\u201d \u201csyndecans,\u201d \u201cglypicans,\u201d \u201cperlecan\/HSPG2,\u201d \u201cversican,\u201d and \u201cdecorin,\u201d with disease- and process-related terms such as \u201cbone metastasis,\u201d \u201cextracellular matrix,\u201d \u201ctumor\u2013bone crosstalk,\u201d \u201cbreast cancer,\u201d \u201cprostate cancer,\u201d \u201cmetastatic niche,\u201d \u201costeolytic metastasis,\u201d \u201costeoblastic metastasis,\u201d \u201cdormancy,\u201d \u201creactivation,\u201d \u201cimmune regulation,\u201d and \u201ctherapy resistance.\u201d Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG\/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease.<\/jats:p>","DOI":"10.3390\/biom16071039","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:55:59Z","timestamp":1784249759000},"page":"1039","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteoglycans as Molecular Regulators of Bone Metastasis: Extracellular Matrix Remodeling, Tumor\u2013Bone Crosstalk, Dormancy, and Therapeutic Opportunities"],"prefix":"10.3390","volume":"16","author":[{"given":"Zoila","family":"Mora Guzm\u00e1n","sequence":"first","affiliation":[{"name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n (SECIHTI), Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"},{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2053-4176","authenticated-orcid":false,"given":"Ibzan Jahzeel","family":"Salvador Ibarra","sequence":"additional","affiliation":[{"name":"Instituto Mexicano del Seguro Social, Hospital General de Zona con Medicina Familiar No. 18, Torre\u00f3n 27220, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6305-5995","authenticated-orcid":false,"given":"Patricia","family":"Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Biomedical Innovation Department, Center for Scientific Research and Higher Education at Ensenada, Ensenada 22860, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-5289","authenticated-orcid":false,"given":"Anah\u00ed Jobeth","family":"Borr\u00e1s Enr\u00edquez","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Tecnol\u00f3gico Nacional de M\u00e9xico\/Instituto Tecnol\u00f3gico de Tuxtla Guti\u00e9rrez, Tuxtla Guti\u00e9rrez 29050, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmar de J\u00e9s\u00fas","family":"D\u00edaz Garc\u00eda","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8502-7098","authenticated-orcid":false,"given":"Hector Alejandro","family":"Cabrera-Fuentes","sequence":"additional","affiliation":[{"name":"R&D Group, Vice Presidency for Scientific Research and Innovation, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia"},{"name":"Divisi\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Tecnol\u00f3gico Nacional de M\u00e9xico\/Instituto Tecnol\u00f3gico de Tijuana, Tijuana 22414, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2182-2540","authenticated-orcid":false,"given":"Mar\u00eda Teresa","family":"Hern\u00e1ndez-Huerta","sequence":"additional","affiliation":[{"name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n (SECIHTI), Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"},{"name":"Centro de Investigaci\u00f3n Facultad de Medicina UNAM-UABJO, Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca, Oaxaca 68020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.tranon.2019.10.012","article-title":"Bone Metastasis: Current State of Play","volume":"13","author":"Turpin","year":"2020","journal-title":"Transl. 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