Rozen Nimrod, Lewinson Dina, Bick Tova, Jacob Zvi C, Stein Haim, Soudry Michael
Department of Anatomy and Cell Biology, The Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, PO Box 9649, Haifa 31096, Israel.
Bone. 2007 Sep;41(3):437-45. doi: 10.1016/j.bone.2007.04.193. Epub 2007 May 8.
Fracture healing presents a sequence of three major stages: inflammation and granulation tissue formation, callus formation and remodeling. Our working hypothesis was that fracture-repair might be enhanced by stimulating proliferation of chondrocytes and osteoblasts in the early stages of fracture healing followed by sequential acceleration of the remodeling process. In the present study we employed a novel device developed by us implementing a standardized fracture in rat tibiae. We investigated the effect of PTH 28-48 or PTH 1-34 alone or in sequence combination with IL-6 together with its soluble receptor (IL-6sR) on fracture repair. PTH 28-48 or PTH 1-34 was applied locally into the hematoma of fractures on days 4, 5 and 6 and IL-6+ its soluble receptor on days 7, 9, and 11. Post-fracture callus volume as measured 14 days post-fracture was increased significantly only by PTH 1-34 (20%; P<0.01). When one of the PTH fragments and IL-6+IL-6sR were applied sequentially callus volume was increased significantly (33%; P<0.01). X-rays radiography at 5 weeks post-fracture showed enlarged callus volume following treatment by either PTH fragments alone, and complete union following the sequential injection of both PTH fragments and IL-6+IL-6sR, only. Only the combination of one of the PTH fragments with IL-6+IL-6sR, as measured 6 weeks post-fracture by three point bending, changed dramatically the quality of the regenerating bone as presented by a 300% increase in mechanical resistance when PTH 1-34 was combined and 200% when PTH 28-48 was combined relative to vehicle-treated fractured bones. We conclude that the sequential application of IL-6+IL-6sR with both PTH fragments has the potential of enhancing fracture healing in long bones and should be further explored in preclinical and in clinical studies.
炎症和肉芽组织形成、骨痂形成以及重塑。我们的工作假设是，在骨折愈合的早期阶段，通过刺激软骨细胞和成骨细胞的增殖，随后依次加速重塑过程，可能会促进骨折修复。在本研究中，我们使用了我们开发的一种新型装置，在大鼠胫骨中制造标准化骨折。我们研究了单独使用甲状旁腺激素28 - 48（PTH 28 - 48）或甲状旁腺激素1 - 34（PTH 1 - 34），或与白细胞介素-6（IL-6）及其可溶性受体（IL-6sR）顺序联合使用对骨折修复的影响。PTH 28 - 48或PTH 1 - 34于骨折后第4、5和6天局部应用于骨折血肿处，IL-6及其可溶性受体于第7、9和11天应用。骨折后14天测量的骨折后骨痂体积仅PTH 1 - 34使其显著增加（20%；P<0.01）。当依次应用其中一种PTH片段和IL-6 + IL-6sR时，骨痂体积显著增加（33%；P<0.01）。骨折后5周的X线摄影显示，单独使用PTH片段治疗后骨痂体积增大，而仅依次注射PTH片段和IL-6 + IL-6sR后骨折完全愈合。骨折后6周通过三点弯曲测量，仅PTH片段之一与IL-6 + IL-6sR联合使用时，再生骨的质量发生了显著变化，当PTH 1 - 34联合使用时机械阻力增加300%，PTH 28 - 48联合使用时增加200%，相对于未治疗的骨折骨。我们得出结论，IL-6 + IL-6sR与两种PTH片段的顺序应用有增强长骨骨折愈合的潜力，应在临床前和临床研究中进一步探索。
