title: Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair.
abstract: BACKGROUND
  Recent studies demonstrate a potentially critical role of matrix metalloproteinases (MMPs) and their inhibitors in the pathophysiology of rotator cuff tears.
  
  
  OBJECTIVE
  Doxycycline-mediated MMP inhibition after rotator cuff repair will improve tendon-to-bone healing.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  Rats (n = 183) underwent acute detachment and repair of the supraspinatus tendon and the animals were divided into 4 groups: In controls (n = 66), the supraspinatus was repaired to its anatomical footprint. In experimental groups, an identical surgery was performed with doxycycline (130 mg/kg/d) administered orally at (1) preoperative day 1 (n = 66), (2) postoperative day (POD) 5 (n = 28), or (3) POD 14 (n = 23). Animals were sacrificed at 5 days, 8 days, 2 weeks, and 4 weeks. Tendon-bone interface was evaluated with histomorphometry. Enzyme-linked immunosorbent assay for local MMP-13 activity was performed at 8 days and 4 weeks. Biomechanical testing of the healing enthesis was performed at 8 days, 2 weeks, and 4 weeks. Serum doxycycline levels were measured at sacrifice. Statistical analysis was performed using unpaired t tests and 2-way analysis of variance (P < .05).
  
  
  RESULTS
  Serum doxycycline levels were significantly higher in all treated groups compared with controls (1830 +/- 835 vs 3 +/- 3 ng/mL, respectively; P < .001). Doxycycline-treated animals demonstrated greater metachromasia and improved collagen organization at the healing enthesis at POD 5 (P < .06), POD 8 (P < .03), and 2 weeks (P < .04). The MMP-13 activity was significantly reduced in doxycycline-treated compared with control animals at POD 8 (6740 +/- 2770 vs 10400 +/- 2930 relative fluorescent units [RFU], respectively; P < .02) but not at 4 weeks (3600 +/- 3280 vs 4530 +/- 2720 RFU, respectively). The healing enthesis of animals started on doxycycline preoperatively or at POD 5 had an increased load to failure compared to controls at 2 weeks (13.6 +/- 1.8 and 13.2 +/- 1.94 N vs 9.1 +/- 2.5 N, respectively; P < .01).
  
  
  CONCLUSIONS
  Modulation of MMP-13 activity after rotator cuff repair may offer a novel biological pathway to augment tendon-to-bone healing.
authors.affiliation: Laboratory for Soft Tissue Research, Hospital For Special Surgery, 535 East 70th Street, New York City, NY 10021, USA. bedia@hss.edu
authors.forename: Asheesh
authors.initials: A
authors.lastname: Bedi
authors.forename: Alice J S
authors.initials: AJ
authors.lastname: Fox
authors.forename: David
authors.initials: D
authors.lastname: Kovacevic
authors.forename: Xeng-Hua
authors.initials: XH
authors.lastname: Deng
authors.forename: Russell F
authors.initials: RF
authors.lastname: Warren
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rodeo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000187:drug effects; D004318:Doxycycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000187:drug effects; D011182:Postoperative Care; D051381:Rats; D017207:Rats, Sprague-Dawley; D017006:Rotator Cuff / Q000601:surgery*; D013710:Tendons / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D004318:Doxycycline