Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice,npj Microgravity

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Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice
npj Microgravity ( IF 5.1 ) Pub Date : 2023-09-18 , DOI: 10.1038/s41526-023-00319-7
Pin Ha _{1,

2} , Jin Hee Kwak ₃ , Yulong Zhang _{4,

5} , Jiayu Shi ₆ , Luan Tran _{1,

2,

6} , Timothy Pan Liu _{1,

2} , Hsin-Chuan Pan ₆ , Samantha Lee _{1,

2} , Jong Kil Kim ₁ , Eric Chen ₆ , Yasaman Shirazi-Fard ₇ , Louis S Stodieck ₈ , Andy Lin ₉ , Zhong Zheng _{1,

2} , Stella Nuo Dong ₆ , Xinli Zhang ₆ , Benjamin M Wu _{2,

4,

5,

6} , Kang Ting ₅ , Chia Soo _{1,

2,

4}

Affiliation

Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, 90089, USA.
Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Forsyth Institute, Cambridge, MA, 02142, USA.
School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, 94035, USA.
BioServe Space Technologies and Aerospace Engineering Sciences, University of Colorado, Boulder, CO, 80303, USA.
Office of Advanced Research Computing, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

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).

中文翻译：

双膦酸盐结合增强了基于 NELL-1 的全身疗法治疗航天飞行引起的小鼠骨质流失的骨特异性

微重力引起的骨质流失会导致每月 1% 的骨矿物质密度损失，这可能是长期太空飞行中的一个关键任务因素。具有成骨和抗吸收双重功能的生物分子疗法有望治疗极度骨质疏松症。我们之前证实 NELL 样分子 1 (NELL-1) 对于骨密度维持至关重要。我们进一步对 NELL-1（NELL-聚乙二醇，或 NELL-PEG）进行聚乙二醇化，将全身递送半衰期从 5.5 小时延长至 15.5 小时。在本研究中，我们使用生物惰性双膦酸盐 (BP) 部分将 NELL-PEG 化学改造为 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，同时保留了 NELL-1 的体外成骨性。此外，BP-NELL-PEG 在小鼠的肝脏、脾脏、肺、脑、心脏、肌肉或卵巢中表现出优异的体内骨特异性，且没有观察到病理变化。最后，我们在一项长期（9 周）骨质疏松症治疗研究中，通过在国际空间站 (ISS) 上以最大动物容量 ( n = 40) 进行太空飞行暴露来测试 BP-NELL-PEG，发现 BP-NELL-PEG 显着改善骨质疏松症。飞行和地面对照小鼠的骨形成增加，且没有明显的不良健康影响。我们的研究结果强调，BP-NELL-PEG 是一种很有前途的治疗方法，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度骨质流失，特别是当由于丧失能力（例如骨折、中风）而无法进行阻力训练时。

更新日期：2023-09-19

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