Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.
Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.
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DOI：
10.1038/s41526-023-00319-7
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发表时间：
2023-09-18
期刊：
影响因子：
5.1
通讯作者：
Soo, Chia
中科院分区：
文献类型：
--
作者：
Ha, Pin;Kwak, Jin Hee;Zhang, Yulong;Shi, Jiayu;Tran, Luan;Liu, Timothy Pan;Pan, Hsin-Chuan;Lee, Samantha;Kim, Jong Kil;Chen, Eric;Shirazi-Fard, Yasaman;Stodieck, Louis S.;Lin, Andy;Zheng, Zhong;Dong, Stella Nuo;Zhang, Xinli;Wu, Benjamin M.;Ting, Kang;Soo, Chia
微重力引起的骨丢失导致每月1%的骨矿物质密度损失，并且可能是长时间航天飞行中的使命关键因素。具有成骨和抗骨吸收双重功能的生物分子疗法有望治疗极端骨质疏松症。我们以前证实，NELL样分子-1（NELL-1）是维持骨密度的关键。我们进一步PEG化NELL-1（NELL-polyethylene glycol，或NELL-PEG）以将全身递送半衰期从5.5小时增加至15.5小时。在这项研究中，我们使用生物惰性双膦酸盐（BP）部分将NELL-PEG化学工程化为BP-NELL-PEG，并特异性靶向骨组织。我们发现与BP的缀合改善了NELL-PEG的羟基磷灰石（HA）结合和蛋白质稳定性，同时在体外保留了NELL-1的成骨性。此外，BP-NELL-PEG显示出上级的体内骨特异性，在小鼠的肝、脾、肺、脑、心脏、肌肉或卵巢中没有可观察到的病理学。最后，我们在一项长期（9周）骨质疏松症治疗研究中，通过国际空间站（ISS）上最大动物容量（n = 40）的太空暴露测试了BP-NELL-PEG，发现BP-NELL-PEG显着增加了飞行和地面对照小鼠的骨形成，没有明显的不良健康影响。我们的研究结果强调了BP-NELL-PEG作为一种有前途的治疗方法，可以减轻地球上长期微重力暴露和肌肉骨骼退化造成的极端骨丢失，特别是当阻力训练由于能力丧失而不可能时（例如，骨折、中风）。
Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1’s osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).
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