Unidad de Gestión Clínica de Endocrinología y Nutrición, CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, RETICEF, 14004, Córdoba, Spain.
Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, RETICEF CIBERFES, 14071, Córdoba, Spain.
Calcif Tissue Int. 2019 Jun;104(6):631-640. doi: 10.1007/s00223-019-00533-0. Epub 2019 Feb 6.
Osteoporosis long-term treatment with nitrogen-containing bisphosphonates, has been associated with uncommon adverse effects, as atypical femoral fractures (AFF). Thus, treatment with teriparatide (TPTD; fragment of human parathyroid hormone; PTH) has been proposed for such patients. Besides its anabolizing effect on bone, TPTD may affect stem-cell mobilization and expansion. Bone marrow mononuclear cells (BMMNC) were isolated from five women that had suffered AFF associated to bisphosphonate treatment, before and after 6 months of TPTD therapy. The presence of mesenchymal stromal cells (CD73, CD90 and CD105 positive cells), gene expression of NANOG, SOX2 and OCT4, proliferation, senescence and capacity to differentiate into osteoblasts and adipocytes were analyzed. After TPTD treatment, BMMNC positive cells for CD73, CD90 and CD105 increased from 6.5 to 37.5% (p < 0.05); NANOG, SOX2 and OCT4 were upregulated, being statistically significant for NANOG (p < 0.05), and cells increased proliferative capacity more than 50% at day 7 (p < 0.05). Senescence was reduced 2.5-fold (p < 0.05), increasing differentiation capacity into osteoblasts and adipocytes, with more than twice mineralization capacity of extracellular matrix or fat-droplet formation (p < 0.05), respectively. Results show that TPTD treatment caused BMMNC "rejuvenation", increasing the number of cells in a more undifferentiated stage, with higher differentiation potency. This effect may favor TPTD anabolic action on bone in such patients with AFF, increasing osteoblast precursor cells. Such response could also arise in other osteoporotic patients treated with TPTD, without previous AFF. Furthermore, our data suggest that TPTD effect on stromal cells may have clinical implications for bone-regenerative medicine. Further studies may deepen on this potential.
骨质疏松症的长期氮杂双膦酸盐治疗与非典型股骨骨折（AFF）等罕见不良影响有关。因此，已经提出使用特立帕肽（TPTD；人甲状旁腺激素片段；PTH）治疗此类患者。除了对骨骼的合成代谢作用外，TPTD 还可能影响干细胞的动员和扩增。从 5 名接受过双膦酸盐治疗且发生 AFF 的女性中分离出骨髓单核细胞（BMMNC），在接受 TPTD 治疗 6 个月前后进行分析。分析了间充质基质细胞（CD73、CD90 和 CD105 阳性细胞）的存在、NANOG、SOX2 和 OCT4 的基因表达、增殖、衰老以及向成骨细胞和脂肪细胞分化的能力。在 TPTD 治疗后，BMMNC 中 CD73、CD90 和 CD105 的阳性细胞从 6.5%增加到 37.5%（p<0.05）；NANOG、SOX2 和 OCT4 上调，NANOG 具有统计学意义（p<0.05），细胞在第 7 天的增殖能力增加了 50%以上（p<0.05）。衰老减少了 2.5 倍（p<0.05），增加了向成骨细胞和脂肪细胞分化的能力，细胞外基质的矿化能力或脂肪滴形成增加了一倍以上（p<0.05）。结果表明，TPTD 治疗使 BMMNC“年轻化”，增加了处于更未分化阶段的细胞数量，分化潜能更高。这种作用可能有利于此类 AFF 患者中 TPTD 对骨骼的合成代谢作用，增加成骨前体细胞。在没有先前 AFF 的情况下，接受 TPTD 治疗的其他骨质疏松症患者也可能出现这种反应。此外，我们的数据表明，TPTD 对基质细胞的作用可能对骨再生医学具有临床意义。进一步的研究可能会深入探讨这一潜力。
