Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China; Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China; National-Local Joint Engineering Laboratory for the Development of Orthopedic Implant Materials, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China.
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; The Institute for Translational Medicine, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China.
Bone. 2021 Sep;150:116012. doi: 10.1016/j.bone.2021.116012. Epub 2021 May 18.
Osteonecrosis resulting from heavy ethanol consumption is one of the major causes of nontraumatic osteonecrosis of the femoral head (ONFH). The underlying pathological and molecular mechanisms remain elusive. In this study, we performed deep RNA sequencing from femoral heads of patients diagnosed with late-stage alcohol-induced ONFH (AIONFH), other types of ONFH and traumatic injury (bone fracture). Genome-wide gene expression analyses identified 690 differentially expressed mRNAs in AIONFH. Gene annotation and pathway analyses revealed significant dysregulated genes involved in hemostasis, angiogenesis and bone remodeling processes from the late-stage AIONFH. Notably, ADH1B, which codes for one of the major alcohol dehydrogenases, is significantly upregulated in AIONFH samples. Further, we found that the ADH1B protein was primarily expressed in smooth muscle cells of the blood vessels, stromal cells and adipocytes of the femoral heads of AIONFH patients; but was absent in other ONFH samples. Our analyses also revealed unique long non-coding RNA (lncRNA) expression profiles and identified novel lncRNAs in AIONFH. In addition, we observed a close co-expression correlation between lncRNAs and mRNAs in AIONFH suggesting that cis-gene regulation represents a major mechanism of action of human femoral lncRNAs. Further, the expression signature of lncRNAs, but not mRNAs, distinguishes AIONFH from other types of ONFH. Taken together, our studies uncovered novel molecular signatures associated with late-stage AIONFH in which the dysregulation of several key signaling pathways within the femoral head may be involved in AIONFH. Subsequently, lncRNAs may serve as potential biomarkers for diagnosis and therapeutic treatment of AIONFH. Further studies are needed to confirm that ADH1B is specifically upregulated in AIONFH and not generally upregulated in patients who consume alcohol excessively.
由大量饮酒导致的骨坏死是引起非创伤性股骨头骨坏死（ONFH）的主要原因之一。其潜在的病理和分子机制仍不清楚。在这项研究中，我们对诊断为晚期酒精性ONFH（AIONFH）、其他类型ONFH 和创伤性损伤（骨折）的患者的股骨头进行了深度 RNA 测序。全基因组基因表达分析鉴定了 AIONFH 中 690 个差异表达的 mRNA。基因注释和途径分析显示，晚期 AIONFH 中涉及止血、血管生成和骨重塑过程的显著失调基因。值得注意的是，编码主要的醇脱氢酶之一的 ADH1B 在 AIONFH 样本中显著上调。此外，我们发现 ADH1B 蛋白主要在 AIONFH 患者股骨头的血管平滑肌细胞、基质细胞和成脂细胞中表达，而在其他 ONFH 样本中不存在。我们的分析还揭示了独特的长非编码 RNA（lncRNA）表达谱，并在 AIONFH 中鉴定了新的 lncRNA。此外，我们观察到 AIONFH 中 lncRNA 和 mRNA 之间存在密切的共表达相关性，这表明顺式基因调控是人类股骨 lncRNA 的主要作用机制。此外，lncRNA 的表达特征而不是 mRNA 的表达特征可将 AIONFH 与其他类型的 ONFH 区分开来。总之，我们的研究揭示了与晚期 AIONFH 相关的新分子特征，其中股骨头内几个关键信号通路的失调可能与 AIONFH 有关。随后，lncRNA 可能成为 AIONFH 诊断和治疗的潜在生物标志物。需要进一步的研究来证实 ADH1B 是特异性地在 AIONFH 中上调，而不是在过度饮酒的患者中普遍上调。
