Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Department of Orthopaedics, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, USA; Department of Bioengineering, Knight Campus for Accelerating Scientific Impact, University of Oregon 1505 Franklin Blvd, Eugene, OR 97403, USA.
Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Department of Orthopaedics, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA.
Bone. 2024 Oct;187:117195. doi: 10.1016/j.bone.2024.117195. Epub 2024 Jul 11.
Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 enhanced osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge produced consistent bone bridging of a critically sized rat femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized to treat a variety of spine disorders.
骨移植手术常用于修复、再生和融合各种骨科手术中的骨骼，包括大的骨缺损和脊柱融合手术。自体移植物是临床金标准，尽管经常使用重组人骨形态发生蛋白（rhBMPs），特别是在困难的临床情况下。然而，rhBMPs 的治疗可能会产生脱靶效应，并增加手术成本，增加患者已经很高的经济和心理负担。最近的研究表明，美国食品和药物管理局批准的免疫抑制剂药物 FK506（他克莫司）也可以通过与抑制剂结合来激活 BMP 途径。本研究检验了以下假设：FK506 作为单一疗法，能否诱导人间充质基质细胞（hMSCs）的成骨分化，并在大鼠节段性骨缺损模型和兔脊柱融合模型中形成功能性骨。FK506 增强了 hMSCs 的体外成骨分化和矿化。单独使用 FK506 处理在胶原海绵上，可产生一致的骨桥接作用，可使大鼠股骨临界大小缺损具有功能机械性能，与天然骨相当。在兔单节段后路脊柱融合模型中，FK506 处理在胶原海绵上成功融合了 L5-L6 椎骨，与 rhBMP-2 治疗的融合率相当。这些数据表明 FK506 能够诱导人细胞和两种具有挑战性的体内模型中的骨形成，并表明 FK506 可用于治疗多种脊柱疾病。
