Sex differences of NF-κB-targeted therapy for mitigating osteoporosis associated with chronic inflammation of bone.

IF 4.7 2区 医学 Q2 CELL & TISSUE ENGINEERING Bone & Joint Research Pub Date : 2024-01-10 DOI:10.1302/2046-3758.131.BJR-2023-0040.R3
Masakazu Toya, Junichi Kushioka, Huaishuang Shen, Takeshi Utsunomiya, Hirohito Hirata, Masanori Tsubosaka, Qi Gao, Simon K-H Chow, Ning Zhang, Stuart B Goodman
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Abstract

Aims: Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice.

Methods: We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR).

Results: Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN.

Conclusion: We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males.

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NF-κB 靶向疗法在缓解与骨骼慢性炎症相关的骨质疏松症方面的性别差异。
目的:转录因子核因子卡巴 B(NF-κB)在所有器官系统的慢性炎症性疾病的发病机制中发挥着重要作用。尽管NF-κB非常重要,但在临床前研究中,NF-κB靶向药物治疗缓解慢性炎症的成功率有限。我们假设,在骨骼慢性炎症期间,性别差异会影响对 NF-κB 治疗的反应。本研究调查了雌雄小鼠慢性炎症期间 NF-κB 诱饵寡脱氧核苷酸(ODN)的治疗效果:我们使用渗透泵连续髓内输送脂多糖污染的聚乙烯颗粒(cPE)诱导小鼠慢性炎症模型。使用显微 CT 和组织形态学分析对标本进行评估。还在体外研究了性别特异性成骨和破骨细胞分化潜能,包括碱性磷酸酶、茜素红、耐酒石酸磷酸酶染色,以及使用反转录聚合酶链反应(RT-PCR)的基因表达:结果:在体内局部给药 NF-κB 诱饵 ODN 能增加男性的骨生成,但不能增加女性的骨生成。两性的骨吸收活性都有所下降。在炎症条件下进行的体外成骨和破骨细胞分化试验并未发现各组之间存在差异。只有男性在接受 ODN 治疗后,成骨细胞的核因子κΒ受体激活剂配体(Rankl)基因表达才会显著下降:我们证明,在慢性炎症的临床前模型中,NF-κB诱饵ODN可增加雄性小鼠的成骨能力,降低雌雄小鼠的骨吸收活性。NF-κB信号可作为涉及骨骼的慢性炎症性疾病的治疗靶点,尤其是在雄性小鼠中。
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来源期刊
Bone & Joint Research
Bone & Joint Research CELL & TISSUE ENGINEERING-ORTHOPEDICS
CiteScore
7.40
自引率
23.90%
发文量
156
审稿时长
12 weeks
期刊介绍: The gold open access journal for the musculoskeletal sciences. Included in PubMed and available in PubMed Central.
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