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Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-\u03b2 activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment (\u201cdrug on\u201d), the impact of drug withdrawal (\u201cdrug off\u201d) implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment (\u201cdrug on\u201d) and subsequent withdrawal (\u201cdrug off\u201d) through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the \u201cdrug on\u201d (Cre-mediated inactivation) and \u201cdrug off\u201d (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells \u00a02019;37:766\u2013778<\/jats:p>\n               <jats:sec>\n                  <jats:title\/>\n               <\/jats:sec>","DOI":"10.1002\/stem.2991","type":"journal-article","created":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T23:40:01Z","timestamp":1550706001000},"page":"766-778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Coordinating Tissue Regeneration Through Transforming Growth Factor-\u03b2 Activated Kinase 1 Inactivation and Reactivation"],"prefix":"10.1093","volume":"37","author":[{"given":"Hsiao Hsin Sung","family":"Hsieh","sequence":"first","affiliation":[{"name":"a Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"b School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"i Experimental Rheumatology Department, Radboud University Medical Center, Nijmegen, The 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