骨吸收和骨形成之间的失衡是导致90%以上多发性骨髓瘤（MM）患者中可见的毁灭性骨溶解损伤和随后的骨折的原因。目前，阻止可溶性Wnt信号通路拮抗剂sclerostin（SOST）和dickkopf-1（DKK1）的Wnt靶向治疗药物已被证明能够在MM的临床前模型中预防骨损失并改善骨强度。在这项研究中，我们展示通过一种新的反-LRP6抗体增强Wnt1类配体信号传导，预防了骨髓瘤引起的骨损失，主要是通过防止骨吸收。当与靶向可溶性Wnt拮抗剂DKK1的药物联合使用时，我们展示出比单独使用反-LRP6治疗更强大的骨结构改善。微CT分析表明，给予反-LRP6 / DKK1联合治疗策略的初始小鼠与对照剂比较，梁状骨体积显着增加。注射5TGM1eGFP小鼠骨髓瘤细胞的小鼠与初始对照小鼠相比，梁状骨体积显着减少。使用反-LRP6 / DKK1组合策略显着提高了5TGM1小鼠的骨体积，提高了111％，这也优于单次反-LRP6治疗。因此，在L4椎体中观察到类似的骨结构变化。因此，与单独使用反-LRP6抗体相比，这种组合策略显着提高了5TGM1小鼠腰椎骨抗折性，为抗折提供了更大的保护。有趣的是，骨体积的这些改善主要是由于骨吸收减少，5TGM1小鼠的骨吸收细胞数和骨表面积显著减少。重要的是，单独或联合使用Wnt靶点药物的Wnt刺激并没有加重肿瘤活动。这项工作提供了一种新的方法，以靶向膜结合和可溶性Wnt通路组分，为多发性骨髓瘤和其他骨破坏性癌症的患者提供优越的骨骼结果。本文受版权保护。版权所有。

An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in pre-clinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-LRP6 antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. MicroCT analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.