Department of Pharmacology, Graduate School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan; Department of Medical and Dental Cooperative Dentistry, Graduate School of Dentistry, Showa University, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan; Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.
Department of Pharmacology, Graduate School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan; Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo, 142-8555, Japan.
J Oral Biosci. 2024 Jun;66(2):391-402. doi: 10.1016/j.job.2024.02.003. Epub 2024 Feb 14.
Some studies have reported that tacrolimus (FK506), an immunosuppressant, may have positive effects on bone formation. However, the precise effects of FK506 on bone repair or osteoblasts remain inadequately elucidated, and limited research has explored the outcomes of its use in an in vivo mouse model. This study aims to examine the effects of FK506 on bone repair and osteoblast functions using bone defect and BMP-2-induced ectopic ossification mouse models, as well as cultured primary mouse osteoblasts treated with FK506.
We established mouse models of femur bone defect and BMP-2-induced ectopic ossification to evaluate the effect of FK506 on new bone formation, respectively. Additionally, primary mouse osteoblasts were cultured with FK506 and examined for gene expressions related to osteoblast differentiation.
While FK506 promoted the repair of bone defect areas in the femur of the bone defect mouse model, it also led to widespread abnormal bone formation outside the intended area. Additionally, following the implantation of a collagen sponge containing BMP-2 into mouse muscle tissue, FK506 was found to promote ectopic ossification and enhance BMP-2-induced osteoblast differentiation in vitro. Our findings also revealed that FK506 increased the number of immature osteoblasts in the absence of BMP-2 without affecting osteoblast differentiation. Furthermore, direct effects were observed, reducing the ability of osteoblasts to support osteoclastogenesis.
These results indicate that FK506 increases new bone formation during bone repair and influences the proliferation of immature osteoblasts, as well as osteoblast-supported osteoclastogenesis.
一些研究报告称，免疫抑制剂他克莫司（FK506）可能对骨形成有积极影响。然而，FK506 对骨修复或成骨细胞的确切影响仍未得到充分阐明，并且有限的研究探讨了其在体内小鼠模型中的应用结果。本研究旨在使用骨缺损和 BMP-2 诱导异位骨化小鼠模型以及用 FK506 处理的培养原代小鼠成骨细胞来研究 FK506 对骨修复和成骨细胞功能的影响。
我们建立了股骨骨缺损和 BMP-2 诱导异位骨化小鼠模型，分别评估 FK506 对新骨形成的影响。此外，用 FK506 培养原代小鼠成骨细胞，并检测与成骨细胞分化相关的基因表达。
虽然 FK506 促进了骨缺损小鼠模型中股骨骨缺损区域的修复，但也导致了预期区域外广泛的异常骨形成。此外，在将含有 BMP-2 的胶原海绵植入小鼠肌肉组织后，发现 FK506 促进了异位骨化，并增强了 BMP-2 诱导的体外成骨细胞分化。我们的研究结果还表明，FK506 在没有 BMP-2 的情况下增加了未成熟成骨细胞的数量，而不影响成骨细胞分化。此外，还观察到直接作用，降低了成骨细胞支持破骨细胞生成的能力。
这些结果表明，FK506 在骨修复过程中增加新骨形成，并影响未成熟成骨细胞的增殖以及成骨细胞支持的破骨细胞生成。
