Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany.
Nephrol Dial Transplant. 2011 Dec;26(12):4115-23. doi: 10.1093/ndt/gfr214. Epub 2011 May 28.
Post-transplantation bone disease is associated with a high degree of morbidity including pain and fractures. Glucocorticoid-induced osteoporosis on top of pre-existing renal osteodystrophy is considered the major pathogenic factor, while the role of non-glucocorticoid immunosuppressants is less well defined.
In this study, we investigated the influence of sirolimus (SRL) versus calcineurin inhibitor (CI)-based immunosuppressive regimens on biomarkers of bone resorption in renal transplant patients. In addition, the impact of SRL, tacrolimus and mycophenolate mofetil (MMF) on osteoclast activation and function was assessed in cell culture systems.
Using this approach, we demonstrated reduced serum levels of bone resorption markers in patients treated with SRL after kidney transplantation compared to a CI-based regimen. In line with this observation, we detected profoundly reduced osteoclast differentiation and subsequently diminished hydroxyapatite resorption in the presence of SRL compared to MMF and tacrolimus in vitro. Moreover, SRL significantly reduced osteoclast precursor proliferation in vitro compared to tacrolimus and led to augmented apoptosis in osteoclast precursors.
Taken together, SRL was shown to inhibit osteoclast formation in vivo and in vitro. SRL thus may have the potential to balance osteoclast promoting effects of glucocorticoids and CI, thereby counteracting the development of accelerated osteoporosis in renal transplant recipients.
移植后骨病与高度发病率相关，包括疼痛和骨折。糖皮质激素诱导的骨质疏松症加上先前存在的肾性骨营养不良被认为是主要的致病因素，而非糖皮质激素免疫抑制剂的作用则不太明确。
在这项研究中，我们研究了西罗莫司（SRL）与钙调神经磷酸酶抑制剂（CI）为基础的免疫抑制方案对肾移植患者骨吸收生物标志物的影响。此外，还在细胞培养系统中评估了 SRL、他克莫司和吗替麦考酚酯（MMF）对破骨细胞激活和功能的影响。
通过这种方法，我们发现在肾移植后接受 SRL 治疗的患者中，与 CI 为基础的方案相比，血清骨吸收标志物水平降低。与这一观察结果一致的是，我们在体外检测到 SRL 与 MMF 和他克莫司相比，可显著减少破骨细胞分化，并随后减少羟磷灰石吸收。此外，SRL 在体外可显著减少破骨细胞前体的增殖，并导致破骨细胞前体的凋亡增加。
总之，SRL 被证明可在体内和体外抑制破骨细胞的形成。因此，SRL 可能具有平衡糖皮质激素和 CI 促进破骨细胞形成的潜力，从而抵消肾移植受者加速骨质疏松症的发展。
