Coordinating Tissue Regeneration Through Transforming Growth Factor-ß Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß 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 ("drug on"), the impact of drug withdrawal ("drug off") 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 ("drug on") and subsequent withdrawal ("drug off") 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 "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established between an enhanced green fluorescent protein-positive/luciferase+ donor and a same-strain nonreporter recipient mouse. The nonreporter mouse received Achilles tendon transection and dorsal burn injury to induce HO formation. Bioluminescence imaging and immunostaining were performed to define the circulatory contribution of immune and mesenchymal cell populations. Histologic analysis showed circulating cells present throughout each stage of the developing HO anlagen. Circulating cells were present at the injury site during the inflammatory phase and proliferative period, with diminished contribution in mature HO. Immunostaining demonstrated that most early circulatory cells were from the innate immune system; only a small population of mesenchymal cells were present in the HO. We demonstrate the time course of the participation of circulatory cells in trauma-induced HO and identify populations of circulating cells present in different stages of HO. These findings further elucidate the relative contribution of local and systemic cell populations to HO.

Association of Hydrocodone Schedule Change With Opioid Prescriptions Following Surgery.

Importance: In 2014, the US Drug Enforcement Administration moved hydrocodone-containing analgesics from schedule III to the more restrictive schedule II to limit prescribing and decrease nonmedical opioid use. The association of this policy change with postoperative prescribing is not well understood. Objective: To examine the hypothesis that the amount of opioids prescribed following surgery is associated with the rescheduling of hydrocodone. Design, Setting, and Participants: An interrupted time series analysis of outpatient opioid prescriptions was conducted to examine the trends in the amount of postoperative opioids filled before and after the schedule change. Opioid prescriptions filled between January 2012 and October 2015 were analyzed using insurance claims data from the Michigan Value Collaborative, which includes data from 75 hospitals across Michigan. A total of 21 955 adult inpatients 18 to 64 years of age who underwent 1 of 19 common elective surgical procedures and filled an opioid prescription within 14 days of discharge to home were eligible for inclusion. Main Outcomes and Measures: The primary outcome was the trends in the mean amount of opioids filled in oral morphine equivalents (OMEs) for the initial postoperative prescriptions before and after the schedule change date of October 6, 2014, compared using interrupted time series and multivariable regression analyses. Secondary outcomes included the total amount of opioids filled and the refill rate for the 30-day postoperative period. Subgroup analyses were performed by hydrocodone prescriptions, nonhydrocodone prescriptions, surgical procedure, and prior opioid use. Results: Data from 21 955 patients undergoing surgical procedures across 75 hospitals and 5120 prescribers were analyzed. Cohorts before and after the schedule change were equivalent with respect to sex (10 197 of 15 791 [64.6%] vs 3966 of 6169 [64.3%] female; P = .69) and mean (SE) age (47.9 [11.2] vs 47.7 [11.3] years; P = .19). After the schedule change, the mean OMEs filled in the initial opioid prescription increased by approximately 35 OMEs (ß = 35.1 [13.2]; P < .01), equivalent to 7 tablets of hydrocodone (5 mg). There were no significant differences in the total OMEs filled during the 30-day postoperative period before and after the schedule change (ß = 18.3 [30.5]; P = .55), but there was a significant decrease in the refill rate (ß = -5.2% [1.3%]; P < .001). Conclusions and Relevance: Changing hydrocodone from schedule III to schedule II was associated with an increase in the amount of opioids filled in the initial prescription following surgery. Opioid-related policies require close follow-up to identify and address early unintended effects given the multitude of competing factors that influence health care professional prescribing behaviors.