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- Title
Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.
- Authors
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
- Abstract
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).
- Subjects
FORMATION flying; BONE density; ENGINEERS; BONE growth; PROTEIN stability; RESISTANCE training; HEART
- Publication
NPJ Microgravity, 2023, Vol 9, Issue 1, p1
- ISSN
2373-8065
- Publication type
Article
- DOI
10.1038/s41526-023-00319-7