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Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis
Xiaogang Wang1,2, Luli Ji3,4, Yuanman Yu3,4
1The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China. wangxiaogang@ecust.edu.cn.
Nature Biomedical Engineering
|July 30, 2026
Summary
Engineered 2-N,6-O-sulfated chitosan (26SCS) restores bone mass and prevents bone loss by balancing resorption and formation. This novel biomaterial surpasses current osteoporosis treatments by targeting key signaling pathways for enhanced bone healing.
Area of Science:
- Biomaterials Science
- Skeletal Biology
- Drug Discovery
Background:
- Current osteoporosis therapies struggle to balance bone resorption and formation, leading to suboptimal outcomes.
- Existing treatments like bisphosphonates have limitations in effectively harmonizing bone metabolism.
Purpose of the Study:
- To develop and evaluate engineered 2-N,6-O-sulfated chitosan (26SCS) as a novel therapeutic agent for osteoporosis.
- To investigate the mechanisms by which 26SCS modulates osteoclastogenesis and osteogenesis.
Main Methods:
- Synthesis and characterization of 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide.
- In vivo studies to assess bone mass restoration and prevention of bone loss.
- Mechanistic studies involving receptor activator of nuclear factor-κB (RANK) and platelet-derived growth factor-BB (PDGF-BB) signaling pathways.
Main Results:
- 26SCS restored 115% bone mass and prevented 66% bone loss, outperforming bisphosphonates.
- 26SCS simultaneously suppressed osteoclastogenesis and promoted vascularized osteogenesis.
- Mechanistically, 26SCS targets K97 in RANK, blocking RANK ligand (RANKL) signaling and enhancing PDGF-BB secretion for angiogenesis-coupled mineralization.
Conclusions:
- 26SCS represents a significant advancement in osteoporosis therapeutics by harmonizing bone metabolism.
- The carboxyl-free design and controlled sulfation of 26SCS overcome limitations of natural glycosaminoglycans.
- This work redefines glycosaminoglycan therapeutics through engineered biomaterials for balanced bone remodeling.
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