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<p>Bone defect healing failure and osteoporosis pose significant challenges to clinical orthopedics and geriatric medicine, while the structural heterogeneity of natural heparan sulfate (HS) hinders the clarification of the functional role of 6-O-sulfation patterns in osteogenesis and its translational application. To address this gap, we developed a structurally defined 6-O-sulfated heparan sulfate glycopolymer (6-O-HS) via reversible addition-fragmentation chain transfer (RAFT) polymerization and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry, establishing an engineering-based synthesis strategy with controllable molecular weight and uniform structure. In vitro experiments showed that 6-O-HS (5&#xa0;µg/mL) significantly enhanced alkaline phosphatase (ALP) activity, osteocalcin (OC) expression, and extracellular matrix mineralization in murine bone marrow mesenchymal stem cells (BMSCs), outperforming conventional HS. RNA sequencing and functional validation revealed that 6-O-HS specifically activated the TGF-β/BMP signaling pathway by upregulating the gene and protein levels of BMP receptors (BMPR1A, BMPR1B, BMPR2) without altering BMP-2 ligand expression. In an ovariectomized (OVX) mouse model, 6-O-HS administration significantly improved bone microarchitecture, increased cortical thickness (Ct.Th) and bone volume fraction (BV/TV), and reduced trabecular separation (Tb.Sp). This study presents a reproducible glycopolymer synthesis and application framework, integrating precision chemical engineering, in vitro mechanistic verification, and in vivo efficacy validation. The framework provides a low-cost, scalable engineering tool for targeted regulation of BMSC osteogenic differentiation, offering novel solutions for bone tissue engineering scaffold development and osteoporosis treatment with broad translational potential in regenerative medicine.</p>

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6-O-Sulfated glycopolymer promotes osteogenesis by amplifying BMP-2 signaling via specific upregulation of BMP receptors

  • 期刊论文

  • 发表日期：

    2026年4月9日

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  • Zhujie Xu,
  • Yi Liu,
  • Jingxiao Chen,
  • Aiguo Gao,
  • Youjia Xu

摘要

Bone defect healing failure and osteoporosis pose significant challenges to clinical orthopedics and geriatric medicine, while the structural heterogeneity of natural heparan sulfate (HS) hinders the clarification of the functional role of 6-O-sulfation patterns in osteogenesis and its translational application. To address this gap, we developed a structurally defined 6-O-sulfated heparan sulfate glycopolymer (6-O-HS) via reversible addition-fragmentation chain transfer (RAFT) polymerization and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry, establishing an engineering-based synthesis strategy with controllable molecular weight and uniform structure. In vitro experiments showed that 6-O-HS (5 µg/mL) significantly enhanced alkaline phosphatase (ALP) activity, osteocalcin (OC) expression, and extracellular matrix mineralization in murine bone marrow mesenchymal stem cells (BMSCs), outperforming conventional HS. RNA sequencing and functional validation revealed that 6-O-HS specifically activated the TGF-β/BMP signaling pathway by upregulating the gene and protein levels of BMP receptors (BMPR1A, BMPR1B, BMPR2) without altering BMP-2 ligand expression. In an ovariectomized (OVX) mouse model, 6-O-HS administration significantly improved bone microarchitecture, increased cortical thickness (Ct.Th) and bone volume fraction (BV/TV), and reduced trabecular separation (Tb.Sp). This study presents a reproducible glycopolymer synthesis and application framework, integrating precision chemical engineering, in vitro mechanistic verification, and in vivo efficacy validation. The framework provides a low-cost, scalable engineering tool for targeted regulation of BMSC osteogenic differentiation, offering novel solutions for bone tissue engineering scaffold development and osteoporosis treatment with broad translational potential in regenerative medicine.