通过抑制硬化蛋白实现多发性骨髓瘤溶解性病变的愈合和骨健康的恢复。

IF 13.5 1区 医学 Q1 HEMATOLOGY
Hayley M Sabol, Aric Anloague, Japneet Kaur, Cecile Bustamante-Gomez, Sharmin Khan, Bethany C Paxton, Mattie R Nester, Jillian Hackney, Marta Diaz-delCastillo, Daniel Mann, Jeffrey B Stambough, C Lowry Barnes, Elena Ambrogini, Alison Frontier, Frank H Ebetino, Syed Naqvi, Frits van Rhee, Christopher P Wardell, Matthew T Drake, Intawat Nookaew, Carolina Schinke, Maurizio Zangari, Jesus Delgado-Calle
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引用次数: 0

摘要

背景:多发性骨髓瘤(MM)与一种使人衰弱的骨病有关,对治疗提出了重大挑战。MM骨病的特点是骨吸收增加和成骨细胞抑制,这阻碍了受损骨的修复。硬化蛋白是Wnt信号的拮抗剂,在MM患者中升高,其与中和抗体(Scl-ab)的抑制已被证明可以恢复MM小鼠模型中的成骨细胞功能。然而,尚不清楚Scl-ab是否能促进骨骼修复,与抗癌药物联合使用时是否能有效控制肿瘤,或改善MM患者的骨骼健康。方法:为了研究这些知识空白,我们使用了临床前MM小鼠模型和患者来源的样本。我们还通过大量和单细胞RNA测序表征了Scl-ab对从小鼠模型中分离的癌症和成骨细胞的影响。最后,我们对Scl-ab改善缓解期MM患者骨骼健康的疗效进行了回顾性分析。结果:Scl-ab促进骨修复,并通过一种抗癌药物抑制肿瘤在各种已建立的MM骨病动物模型中。MM肿瘤抑制Wnt信号,减少成骨细胞和骨car细胞的数量,而Scl-ab治疗逆转了这些作用。在缓解期MM患者中,即使与维持性化疗联合使用,Scl-ab治疗也能增加骨量并修复骨。结论:我们的研究结果强调了Scl-ab的强大骨愈合作用及其作为抗癌治疗辅助的潜力,为改善MM患者的临床结果和生活质量提供了有希望的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Healing of lytic lesions and restoration of bone health in multiple myeloma through sclerostin inhibition.

Background: Multiple myeloma (MM) is associated with a debilitating bone disease that poses significant therapeutic challenges. MM bone disease is characterized by increased bone resorption and suppression of osteoblasts, which hinders the repair of damaged bone. Sclerostin, an antagonist of Wnt signaling, is elevated in MM patients, and its inhibition with a neutralizing antibody (Scl-ab) has been shown to restore osteoblast function in mouse models of MM. However, it remains unclear whether Scl-ab can promote skeletal repair, enable effective tumor control when combined with anti-cancer agents, or improve bone health in MM patients.

Methods: To investigate these knowledge gaps, we used preclinical MM mouse models and patient-derived samples. We also characterize the impact of Scl-ab on cancer and osteoblastic cells isolated from mouse models through bulk and single-cell RNA sequencing. Lastly, we performed a retrospective analysis of the efficacy of Scl-ab to improve bone health in patients with MM in remission.

Results: Scl-ab promoted skeletal repair and enabled tumor suppression by an anti-cancer agent in various animal models of established MM bone disease. MM tumors suppressed Wnt signaling and decreased the number of osteoblasts and osteo-CAR cells, and treatment with Scl-ab reversed these effects. Treatment with Scl-ab increased bone mass and repaired bone in patients with MM in remission, even when combined with maintenance chemotherapy.

Conclusions: Our findings highlight the potent bone-healing effects of Scl-ab and its potential as an adjuvant to anti-cancer therapy, offering a promising approach to improve clinical outcomes and the quality of life for MM patients.

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来源期刊
CiteScore
12.60
自引率
7.30%
发文量
97
审稿时长
6 weeks
期刊介绍: Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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