Hamrick Mark W, Arounleut Phonepasong, Kellum Ethan, Cain Matthew, Immel David, Liang Li-Fang
Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
J Trauma. 2010 Sep;69(3):579-83. doi: 10.1097/TA.0b013e3181c451f4.
Myostatin (GDF-8) is known as a potent inhibitor of muscle growth and development, and myostatin is also expressed early in the fracture healing process. The purpose of this study was to test the hypothesis that a new myostatin inhibitor, a recombinant myostatin propeptide, can enhance the repair and regeneration of both muscle and bone in cases of deep penetrant injury.
We used a fibula osteotomy model with associated damage to lateral compartment muscles (fibularis longus and brevis) in mice to test the hypothesis that blocking active myostatin with systemic injections of a recombinant myostatin propeptide would improve muscle and bone repair. Mice were assigned to two treatment groups after undergoing a fibula osteotomy: those receiving either vehicle (saline) or recombinant myostatin propeptide (20 mg/kg). Mice received one injection on the day of surgery, another injection 5 days after surgery, and a third injection 10 days after surgery. Mice were killed 15 days after the osteotomy procedure. Bone repair was assessed using microcomputed tomography (micro-CT) and histologic evaluation of the fracture callus. Muscle healing was assessed using Masson trichrome staining of the injury site, and image analysis was used to quantify the degree of fibrosis and muscle regeneration.
Three propeptide injections over a period of 15 days increased body mass by 7% and increased muscle mass by almost 20% (p < 0.001). Micro-CT analysis of the osteotomy site shows that by 15 days postosteotomy, bony callus tissue was observed bridging the osteotomy gap in 80% of the propeptide-treated mice but only 40% of the control (vehicle)-treated mice (p < 0.01). Micro-CT quantification shows that bone volume of the fracture callus was increased by ∼ 30% (p < 0.05) with propeptide treatment, and the increase in bone volume was accompanied by a significant increase in cartilage area (p = 0.01). Propeptide treatment significantly decreased the fraction of fibrous tissue in the wound site and increased the fraction of muscle relative to fibrous tissue by 20% (p < 0.01).
Blocking myostatin signaling in the injured limb improves fracture healing and enhances muscle regeneration. These data suggest that myostatin inhibitors may be effective for improving wound repair in cases of orthopaedic trauma and extremity injury.
肌肉生长抑制素（生长分化因子8）是一种已知的肌肉生长和发育的强效抑制剂，且在骨折愈合过程早期也有表达。本研究的目的是验证一种新的肌肉生长抑制素抑制剂——重组肌肉生长抑制素前肽，能否在深度穿透伤情况下促进肌肉和骨骼的修复与再生这一假说。
我们使用小鼠腓骨截骨模型，该模型伴有外侧肌间隔肌肉（腓骨长肌和腓骨短肌）损伤，以验证通过全身注射重组肌肉生长抑制素前肽阻断活性肌肉生长抑制素可改善肌肉和骨骼修复这一假说。小鼠在接受腓骨截骨术后被分为两个治疗组：一组接受赋形剂（生理盐水），另一组接受重组肌肉生长抑制素前肽（20毫克/千克）。小鼠在手术当天接受一次注射，术后5天接受第二次注射，术后10天接受第三次注射。在截骨术后15天处死小鼠。使用微型计算机断层扫描（显微CT）和骨折痂的组织学评估来评估骨修复情况。使用损伤部位的Masson三色染色评估肌肉愈合情况，并通过图像分析量化纤维化程度和肌肉再生情况。
在15天内进行三次前肽注射使体重增加了7%，肌肉质量增加了近20%（p<0.001）。对截骨部位的显微CT分析显示，截骨术后15天时，在接受前肽治疗的小鼠中，有80%观察到骨痂组织桥接了截骨间隙，而在接受对照（赋形剂）治疗的小鼠中这一比例仅为40%（p<0.01）。显微CT定量分析显示，前肽治疗使骨折痂的骨体积增加了约30%（p<0.05），并且骨体积的增加伴随着软骨面积的显著增加（p = 0.01）。前肽治疗显著降低了伤口部位纤维组织的比例，相对于纤维组织，肌肉比例增加了20%（p<0.01）。
阻断受伤肢体中的肌肉生长抑制素信号可改善骨折愈合并增强肌肉再生。这些数据表明，肌肉生长抑制素抑制剂可能对改善骨科创伤和肢体损伤情况下的伤口修复有效。
