Hurtgen Brady J, Henderson Beth E P, Ward Catherine L, Goldman Stephen M, Garg Koyal, McKinley Todd O, Greising Sarah M, Wenke Joseph C, Corona Benjamin T
Extremity Trauma and Regenerative Medicine Task Area, US Army Institute of Surgical Research, 3698 Chambers Pass, BHT1, Fort Sam Houston, TX, 78234, USA.
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
BMC Musculoskelet Disord. 2017 Jun 12;18(1):253. doi: 10.1186/s12891-017-1617-y.
Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration.
We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle).
The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production CONCLUSION: Collectively, these findings support the administration of FK506 to ameliorate healing of fractures with severe muscle trauma comorbidity. The results suggest one potential mechanism of action is a reduction in local T lymphocytes within the injured musculoskeletal tissue, though other mechanisms to include direct osteogenic effects of FK506 require further investigation.
因肌肉创伤或疾病导致的局部炎症加剧与骨再生受损有关。
我们假设，FK506是一种经美国食品药品监督管理局（FDA）批准的具有神经营养和成骨作用的免疫调节化合物，它将挽救雄性（约4个月大）Lewis大鼠因伴随肌肉创伤而受损的骨折愈合早期阶段。在内源性愈合的胫骨截骨术后，用髓内针固定，然后全身给予FK506（1mg/kg；腹腔注射）或生理盐水，持续14天，胫骨前肌（TA）要么不损伤，要么造成体积性肌肉损失损伤（从肌肉中三分之一处取6mm全层活检组织）。
本研究的主要观察结果为：1）伴随的TA肌肉创伤会损害损伤后28天胫骨力学性能的恢复；2）FK506给药挽救了伴随TA肌肉创伤时胫骨力学性能的恢复，但并未增强单纯截骨术（无肌肉创伤）的力学恢复；3）创伤后3天，创伤肌肉组织中的T淋巴细胞和巨噬细胞数量因创伤而增加，并因FK506而减少；4）损伤后14天，FK506使骨折痂内的T淋巴细胞数量减少，但巨噬细胞数量未减少。FK506并未改善TA肌肉等长扭矩的产生。
总的来说，这些发现支持使用FK506来改善伴有严重肌肉创伤合并症的骨折愈合。结果表明一种潜在的作用机制是减少受伤肌肉骨骼组织内的局部T淋巴细胞，不过包括FK506直接成骨作用在内的其他机制仍需进一步研究。
