{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:38:55Z","timestamp":1782315535078,"version":"3.54.5"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":1152,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":505,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Biomechanics and Biomaterials Research Center grant"},{"name":"Biomedical Research Grant"},{"name":"Start-Up from Mechanical and Energy Engineering, IUPUI"},{"DOI":"10.13039\/100007268","name":"Washington University in St. Louis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007268","name":"Washington University in St. Louis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Intervertebral disc (IVD) degeneration is a leading cause of low back pain, characterized by accelerated extracellular matrix breakdown and IVD height loss, but there is no approved pharmacological therapeutic. Deletion of Wnt ligand competitor Lrp5 induces IVD degeneration, suggesting that Wnt signaling is essential for IVD homeostasis. Therefore, the IVD may respond to neutralization of Wnt ligand competitors sost(gene)\/sclerostin(protein) and\/or dickkopf-1 (dkk1). Anti-sclerostin antibody (scl-Ab) is an FDA-approved bone therapeutic that activates Wnt signaling. We aimed to (i) determine if pharmacological neutralization of sclerostin, dkk1, or their combination would stimulate Wnt signaling and augment IVD structure and (ii) determine the prolonged adaptation of the IVD to global, persistent deletion of sost. Nine-week-old C57Bl\/6J female mice (n\u00a0=\u00a06\u20137\/group) were subcutaneously injected 2\u00d7\/week for 5.5\u2009weeks with scl-Ab (25\u2009mg\/kg), dkk1-Ab (25\u2009mg\/kg), 3:1 scl-Ab\/dkk1-Ab (18.75:6.25\u2009mg\/kg), or vehicle (veh). Separately, IVD of sost KO and wild-type (WT) mice (n\u00a0=\u00a08\/group) were harvested at 16\u2009weeks of age. First, compared with vehicle, injection of scl-Ab, dkk1-Ab, and 3:1 scl-Ab\/dkk1-Ab similarly increased lumbar IVD height and \u03b2-catenin gene expression. Despite these similarities, only injection of scl-Ab alone strengthened IVD mechanical properties and decreased heat shock protein gene expressions. Genetically and compared with WT, sost KO enlarged IVD height, increased proteoglycan staining, and imbibed IVD hydration. Notably, persistent deletion of sost was compensated by upregulation of dkk1, which consequently reduced the cell nuclear fraction for Wnt signaling co-transcription factor \u03b2-catenin in the IVD. Lastly, RNA-sequencing pathway analysis confirmed the compensatory suppression of Wnt signaling and revealed a reduction of cellular stress-related pathways. Together, suppression of sost\/sclerostin or dkk1 each augmented IVD structure by stimulating Wnt signaling, but scl-Ab outperformed dkk1-Ab in strengthening the IVD. Ultimately, postmenopausal women prescribed scl-Ab injections to prevent vertebral fracture may also benefit from a restoration of IVD height and health. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>\n                  <jats:p>Abstract<\/jats:p>\n                  <jats:p>Suppression of Wnt signaling inhibitors by genetic or pharmacological approaches promoted intervertebral disc structure, strength, and hydration. However, persistent activation of Wnt signaling induced a compensatory upregulation of other Wnt signaling inhibitors that shifted IVD cells toward a mature NP cell phenotype. AF = annulus fibrosus; NC = notochordal cell; NP = nucleus pulposus; PG = proteoglycan.<\/jats:p>","DOI":"10.1002\/jbmr.4546","type":"journal-article","created":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T09:50:05Z","timestamp":1647078605000},"page":"1156-1169","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Suppression of Sost\/Sclerostin and Dickkopf-1 Augment Intervertebral Disc Structure in Mice"],"prefix":"10.1093","volume":"37","author":[{"given":"Tori","family":"Kroon","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering IUPUI Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neharika","family":"Bhadouria","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering Purdue University West Lafayette IN 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