{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:02:05Z","timestamp":1792792925712,"version":"4.5.0"},"reference-count":186,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"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. Endocrinol."],"abstract":"<jats:p>Osteoporosis is a systemic skeletal disorder characterized by progressive loss of bone mass and deterioration of microarchitectural integrity. Traditionally, its pathogenesis has been attributed primarily to an imbalance in the number and activity of osteoblasts and osteoclasts. However, emerging evidence has uncovered a critical bidirectional interdependence between the integrity of the extracellular matrix (ECM) and the functional homeostasis of the intracellular lysosomal system\u2014an axis increasingly recognized as the \u201cbone matrix\u2013lysosome crosstalk.\u201d Despite its apparent importance, the central role of this regulatory circuitry in bone homeostasis and the mechanisms through which it becomes disrupted under pathological conditions remain insufficiently defined.This review synthesizes current advances regarding the cell type\u2013specific functions of lysosomes across distinct bone cell populations and further examines how the ECM, as a dynamic microenvironment, exerts reciprocal control over lysosomal biogenesis and activity. We highlight how the biochemical composition and biophysical properties of the ECM govern lysosomal acidification, metabolic coupling, and degradative capacity with remarkable precision. During the progression of osteoporosis, structural compromise of the ECM and lysosomal dysfunction reinforce one another, establishing a self-amplifying pathological loop that accelerates the collapse of the bone microenvironment. Recognizing this reciprocal deterioration, we propose that restoring the dynamic equilibrium of the \u201cECM\u2013lysosome axis\u201d may represent a mechanistic pivot for reversing osteoporotic degeneration. Interventions targeting lysosomal function, reconstructing the bone ECM, and employing nanomedicine-enabled organelle-specific delivery hold particular promise for advancing precision therapeutics in osteoporosis.<\/jats:p>","DOI":"10.3389\/fendo.2025.1698404","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:34:27Z","timestamp":1768286067000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Chang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqian","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guomin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e081250","DOI":"10.1136\/bmj-2024-081250","article-title":"Advances in the management of osteoporosis","volume":"390","author":"Hoong","year":"2025","journal-title":"BMJ."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1222129","article-title":"The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review","volume":"14","author":"Xu","year":"2023","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41514-025-00269-2","article-title":"Global epidemiology and burden of osteoporosis among postmenopausal women: insights from the Global Burden of Disease Study 2021","volume":"11","author":"Liang","year":"2025","journal-title":"NPJ Aging."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2021.1369","article-title":"Discontinuing denosumab: can it be done safely? 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