{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T23:29:04Z","timestamp":1775863744249,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T00:00:00Z","timestamp":1555459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH R21 TR001751-02"],"award-info":[{"award-number":["NIH R21 TR001751-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoinductive bone morphogenetic proteins (BMPs), including BMP-2, have a unique capability of mediating bone formation both in orthotopic and ectopic locations. Immunosuppresive macrolides have been shown to potentiate BMP-2 activity through FKBP12, but these have yet to translate to effective osteoinductive therapies. Herein, we show the osteogenic activity of FK506 as a stand-alone agent in direct comparison to BMP-2 both in vitro and in vivo. FK506 was capable of producing stand-alone alkaline phosphatase induction in C2C12 cells comparable to that seen with rhBMP-2. FK506 treatment activated the BMP receptor, as shown by increased pSmad1\/5 levels, and produced significantly higher mRNA levels of the early response genes in BMP and TGF-\u03b2 pathways. Additionally, the FK506 induction of alkaline phosphatase was shown to be resistant to Noggin treatment. In vivo osteogenic activity of FK506 was tested by local delivery on a collagen sponge in an ectopic subcutaneous implantation model in the rat. Dose responses of FK506 showed increasing levels of ectopic mineralization comparable to the mineral volume produced by BMP-2 delivery. These findings suggest that the use of FK506 can enhance osteoblastic differentiation in vitro and can induce mineralization when delivered locally in vivo.<\/jats:p>","DOI":"10.3390\/ijms20081900","type":"journal-article","created":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T07:58:09Z","timestamp":1555487889000},"page":"1900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["FK506 Induces Ligand-Independent Activation of the Bone Morphogenetic Protein Pathway and Osteogenesis"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-1187","authenticated-orcid":false,"given":"Sreedhara","family":"Sangadala","sequence":"first","affiliation":[{"name":"Atlanta VA Medical Center, Decatur, GA 30033, USA"},{"name":"Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Devereaux","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6547-9495","authenticated-orcid":false,"given":"Steven","family":"Presciutti","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center, Decatur, GA 30033, USA"},{"name":"Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Boden","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nick","family":"Willett","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center, Decatur, GA 30033, USA"},{"name":"Department of Orthopaedics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,17]]},"reference":[{"key":"ref_1","first-page":"3","article-title":"The nature of pseudoarthrosis. 1968","volume":"284","author":"DePalma","year":"1992","journal-title":"Clin. 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