Larraz-Prieto Beatriz, Lind Louise Hjorth, Olesen Jacob Bastholm, Azfer Asim, Hansen Morten Svarer, Frost Morten, Jafari Abbas, Ralston Stuart H, Søe Kent, Alonso Nerea
Rheumatic Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
Bone Joint Res. 2025 May 16;14(5):463-476. doi: 10.1302/2046-3758.145.BJR-2024-0167.R1.
To investigate the role of CXCR4 in response to teriparatide (TPTD) treatment in osteoblasts and osteoclasts.
Primary murine and human osteoblasts and osteoclasts, MC3T3 cell lines, and hMSC-TERT4 cell lines were treated with TPTD and/or AMD3100, a pharmacological inhibitor of CXCR4. Changes in gene expression, osteoblast viability, mobility, mineralization capacity, and alkaline phosphatase activity were investigated. Osteoclastogenesis and cell fusion were also assessed in response to both treatments.
TPTD increased messenger RNA levels of in all stages of both murine and human osteoblast differentiation. Mineralization analysis showed that CXCR4 was involved in bone matrix formation in response to TPTD. Alkaline phosphatase activity was also impaired by CXCR4 inhibition at early stages of osteoblast differentiation, while it was promoted at late stages, suggesting that CXCR4 could produce a delay in osteoblast maturation. Moreover, we also found a direct activation of osteoclastogenesis after TPTD treatment in murine and human osteoclasts. This process seems to involve CXCR4 activity, since AMD3100-induced CXCR4 inhibition led to a reduction in both murine and human osteoclastogenesis. This process, however, could not be prevented by TPTD treatment.
Our results suggest that is a responsive gene to TPTD treatment, involved in the regulation of osteoblast and osteoclast generation and function. Further in vivo studies are required to confirm this role, and to determine whether pharmacological strategies targeting CXCR4 could potentially improve the treatment outcome for osteoporotic patients.
研究CXCR4在成骨细胞和破骨细胞对特立帕肽（TPTD）治疗反应中的作用。
用TPTD和/或AMD3100（CXCR4的药理学抑制剂）处理原代小鼠和人成骨细胞、破骨细胞、MC3T3细胞系和hMSC-TERT4细胞系。研究基因表达、成骨细胞活力、迁移能力、矿化能力和碱性磷酸酶活性的变化。还评估了两种处理对破骨细胞生成和细胞融合的影响。
TPTD增加了小鼠和人成骨细胞分化各阶段的信使核糖核酸水平。矿化分析表明，CXCR4参与了对TPTD反应的骨基质形成。在成骨细胞分化早期，CXCR4抑制也会损害碱性磷酸酶活性，而在晚期则会促进其活性，这表明CXCR4可能会延迟成骨细胞成熟。此外，我们还发现TPTD处理后小鼠和人破骨细胞中破骨细胞生成直接被激活。这个过程似乎涉及CXCR4活性，因为AMD3100诱导的CXCR4抑制导致小鼠和人破骨细胞生成均减少。然而，TPTD处理无法阻止这个过程。
我们的结果表明， 是对TPTD治疗有反应的基因，参与成骨细胞和破骨细胞生成及功能的调节。需要进一步的体内研究来证实这一作用，并确定靶向CXCR4的药理学策略是否可能潜在改善骨质疏松症患者的治疗效果。
