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

作者：Pin Ha, Jin Hee Kwak, Yulong Zhang, Jiayu Shi, Luan Tran, Timothy Pan Liu, Hsin-Chuan Pan, Samantha Lee, Jong Kil Kim, Eric Chen, Yasaman Shirazi‐Fard, Louis Stodieck, Andy Lin, Zhong Zheng, Stella Nuo Dong, Xinli Zhang, Benjamin M. Wu, Kang Ting, Chia Soo · 发表于：npj Microgravity · 年份：2023 · DOI：10.1038/s41526-023-00319-7 · 被引用次数：22 · 研究领域：Spaceflight effects on biology、Radiation Therapy and Dosimetry、Mitochondrial Function and Pathology

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 ...