Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA.
Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA.
Bone. 2023 Dec;177:116891. doi: 10.1016/j.bone.2023.116891. Epub 2023 Sep 3.
Severe osteoporosis is often treated with one of three Food and Drug Administration (FDA)-approved osteoanabolics. These drugs act by (1) parathyroid hormone (PTH) receptor stimulation using analogues to PTH (teriparatide) or PTH-related peptide (abaloparatide) or by (2) monoclonal antibody neutralization of sclerostin, an innate Wnt inhibitor (Scl-mAb, romosozumab-aqqg). The efficacies of both strategies wane over time. The transcription factor Nmp4 (Nuclear Matrix Protein 4) is expressed in all tissues yet mice lacking this gene are healthy and exhibit enhanced PTH-induced bone formation. Conditional deletion of Nmp4 in mesenchymal stem progenitor cells (MSPCs) phenocopies the elevated response to PTH in global Nmp4 mice. However, targeted deletion in later osteoblast stages does not replicate this response. In this study we queried whether loss of Nmp4 improves Scl-mAb potency. Experimental cohorts included global Nmp4 and Nmp4 littermates and three conditional knockout models. Nmp4-floxed (Nmp4) mice were crossed with mice harboring one of three Cre-drivers (i) Prx1Cre+ targeting MSPCs, (ii) BglapCre+ (mature osteocalcin-expressing osteoblasts), and (iii) Dmp1Cre+ (osteocytes). Female mice were treated with Scl-mAb or 0.9 % saline vehicle for 4 or 7 weeks from 10 weeks of age. Skeletal response was assessed using micro-computed tomography, dual-energy X-ray absorptiometry, bone histomorphometry, and serum analysis. Global Nmp4 mice exhibited enhanced Scl-mAb-induced increases in trabecular bone in the femur and spine and a heightened increase in whole body areal bone mineral density compared to global Nmp4 controls. This improved Scl-mAb potency was primarily driven by enhanced increases in bone formation. Nmp4;PrxCre+ mice showed an exaggerated Scl-mAb-induced increase in femoral bone but not in the spine since Prrx1 is not expressed in vertebra. The Nmp4;BglapCre+ and Nmp4;Dmp1Cre+ mice did not exhibit an improved Scl-mAb response. We conclude that Nmp4 expression in MSPCs interferes with the bone anabolic response to anti-sclerostin therapy.
严重骨质疏松症通常采用美国食品药品监督管理局（FDA）批准的三种骨合成代谢药物之一进行治疗。这些药物的作用机制为：（1）通过甲状旁腺激素（PTH）受体刺激，使用 PTH 类似物（特立帕肽）或 PTH 相关肽（abaloparatide）；或（2）通过单克隆抗体中和硬化蛋白（Scl），一种天然的 Wnt 抑制剂（Scl-mAb，romosozumab-aqqg）。这两种策略的疗效随时间推移而减弱。转录因子 Nmp4（核基质蛋白 4）在所有组织中表达，但缺乏这种基因的小鼠健康且表现出增强的 PTH 诱导的骨形成。在间充质干细胞祖细胞（MSPCs）中条件性缺失 Nmp4 可模拟全局 Nmp4 小鼠中对 PTH 的升高反应。然而，在后期成骨细胞阶段的靶向缺失并未复制这种反应。在这项研究中，我们探讨了缺失 Nmp4 是否能提高 Scl-mAb 的效力。实验队列包括全局 Nmp4 和 Nmp4 同窝仔以及三种条件性敲除模型。Nmp4 基因敲入（Nmp4）小鼠与携带三种 Cre 驱动子之一的小鼠交配：（i）Prx1Cre+，靶向 MSPCs；（ii）BglapCre+（成熟骨钙素表达的成骨细胞）；和（iii）Dmp1Cre+（破骨细胞）。从 10 周龄开始，雌性小鼠接受 Scl-mAb 或 0.9%生理盐水载体治疗 4 或 7 周。使用微计算机断层扫描、双能 X 射线吸收仪、骨组织形态计量学和血清分析评估骨骼反应。与全局 Nmp4 对照相比，全局 Nmp4 小鼠表现出 Scl-mAb 诱导的骨小梁骨增加、整个身体面积骨密度增加和骨形成增加。这种 Scl-mAb 效力的提高主要是由于骨形成的增加。Nmp4;PrxCre+ 小鼠在股骨中表现出 Scl-mAb 诱导的增加，但在脊柱中没有增加，因为 Prrx1 不在椎骨中表达。Nmp4;BglapCre+ 和 Nmp4;Dmp1Cre+ 小鼠没有表现出对 Scl-mAb 的改善反应。我们得出结论，MSPCs 中的 Nmp4 表达会干扰抗硬化蛋白治疗的骨合成代谢反应。
