ArticleTissue engineering. Part A2017
Growth Differentiation Factor 5-Mediated Enhancement of Chondrocyte Phenotype Is Inhibited by Heparin: Implications for the Use of Heparin in the Clinic and in Tissue Engineering Applications.
Article in Tissue engineering. Part A, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
19 citing papers in PubMed, 34 citations in OpenAlex.
- Dichotomous SMAD2/3 regulation and selective antihypertrophic activity of heparin during in vitro chondrogenesis of mesenchymal stromal cells.Cellular & molecular biology letters · 2026Article
- Heparan sulfate as a central modulator of growth factor dynamics in tissue regeneration.APL bioengineering · 2025Article
- Enthesitis on Chip - A Model for Studying Acute and Chronic Inflammation of the Enthesis and its Pharmacological Treatment.Advanced healthcare materials · 2024Article
- Article
- Comparative in vitro treatment of mesenchymal stromal cells with GDF-5 and R57A induces chondrogenic differentiation while limiting chondrogenic hypertrophy.Journal of experimental orthopaedics · 2023Article
- Formation and characterization of BMP2/GDF5 and BMP4/GDF5 heterodimers.BMC biology · 2023Article
- Current Insights Into the Maintenance of Structure and Function of Intervertebral Disc: A Review of the Regulatory Role of Growth and Differentiation Factor-5.Frontiers in pharmacology · 2022Review
- Growth factor and macromolecular crowding supplementation in human tenocyte culture.Biomaterials and biosystems · 2021Article
- Osteogenic and Angiogenic Properties of Heparin as a System for Delivery of Biomolecules for Bone Bioengineering: a Brief Critical Review.Biochemistry (Moscow) Supplement. Series B, Biomedical chemistry · 2021Article
- Review
- The GDF-5 mutant M1673 exerts robust anabolic and anti-catabolic effects in chondrocytes.Journal of cellular and molecular medicine · 2020Article
- GDF5 induces TBX3 in a concentration dependent manner - on a gold nanoparticle gradient.Heliyon · 2020Article
- Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function.Frontiers in cell and developmental biology · 2020Review
- Heparin-Modified Amniotic Membrane Combined With Growth Factors for Promoting Corneal Wound Healing After Alkali Burn.Frontiers in bioengineering and biotechnology · 2020Article
- Fully Synthetic Heparan Sulfate-Based Neural Tissue Construct That Maintains the Undifferentiated State of Neural Stem Cells.ACS chemical biology · 2019Article
- Comparison of the effect of growth factors on chondrogenesis of canine mesenchymal stem cells.The Journal of veterinary medical science · 2019Article
- Microparticle-mediated sequestration of cell-secreted proteins to modulate chondrocytic differentiation.Acta biomaterialia · 2018Article
- The Good the Bad and the Ugly of Glycosaminoglycans in Tissue Engineering Applications.Pharmaceuticals (Basel, Switzerland) · 2017Review
- Heparin, Heparan Sulphate and the TGF-β Cytokine Superfamily.Molecules (Basel, Switzerland) · 2017Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The highly sulfated glycosaminoglycan (GAG) heparin is widely used in the clinic as an anticoagulant, and researchers are now using it to enhance stem cell expansion/differentiation protocols, as well as to improve the delivery of growth factors for tissue engineering (TE) strategies. Growth differentiation factor 5 (GDF5) belongs to the bone morphogenetic protein family of proteins and is vital for skeletal formation; however, its interaction with heparin and heparan sulfate (HS) has not been studied. We identify GDF5 as a novel heparin/HS binding protein and show that HS proteoglycans are vital in localizing GDF5 to the cell surface. Clinically relevant doses of heparin (≥10 nM), but not equivalent concentrations of HS, were found to inhibit GDF5's biological activity in both human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures and the skeletal cell line ATDC5. We also found that heparin inhibited both GDF5 binding to cell surface HS and GDF5-induced induction of Smad 1/5/8 signaling. Furthermore, GDF5 significantly increased aggrecan gene expression in chondrocyte pellet cultures, without affecting collagen type X expression, making it a promising target for the TE of articular cartilage. Importantly, this study may explain the variable (and disappointing) results seen with heparin-loaded biomaterials for skeletal TE and the adverse skeletal effects reported in the clinic following long-term heparin treatment. Our results caution the use of heparin in the clinic and in TE applications, and prompt the transition to using more specific GAGs (e.g., HS derivatives), with better-defined structures and fewer off-target effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.