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  • Review Article
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Restoring articular cartilage: insights from structure, composition and development

Nature Reviews Rheumatology volume 21, pages 291–308 (2025)Cite this article

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Abstract

Articular cartilage can withstand substantial compressive and shear forces within the joint and also reduces friction during motion. The exceptional mechanical properties of articular cartilage stem from its highly organized extracellular matrix (ECM). The ECM is composed mainly of collagen type II and is pivotal in conferring mechanical durability to the tissue within its proteoglycan-rich matrix. Articular cartilage is prone to injury and degeneration, and current treatments often fail to restore the mechanical function of this tissue. A key challenge is replicating the intricate collagen–proteoglycan network, which is essential for the long-lasting restoration and mechanical durability of the tissue. Understanding articular cartilage development, which arises between late embryonic and early juvenile development, is vital for the creation of durable therapeutic strategies. The development of the articular ECM involves the biosynthesis, fibrillogenesis and self-assembly of the collagen type II network, which, along with proteoglycans and minor ECM components, shapes the architecture of adult articular cartilage. A deeper understanding of these processes could inform biomaterial-based therapies aimed at improving therapeutic outcomes. Emerging biofabrication technologies offer new opportunities to integrate developmental principles into the creation of durable articular cartilage implants. Bridging fundamental biology with innovative engineering offers novel approaches to generating more-durable 3D implants for articular cartilage restoration.

Key points

  • Articular cartilage is a highly anisotropic tissue that is characterized by depth-dependent collagen fibre orientation, which provides the tissue with its unique biomechanical properties.

  • The collagen architecture of the articular cartilage forms during late fetal and postnatal development in response to biomechanical stimuli and tissue growth.

  • Collagen interacts with the surrounding extracellular matrix (ECM), including aggrecan, by limiting the water-swelling pressure caused by negatively charged glycosaminoglycans, thereby enhancing cartilage resilience.

  • Small proteoglycans and (glyco)proteins promote tissue cohesion and stability by regulating fibrillogenesis and connecting various ECM components together.

  • Achieving native-like collagen anisotropy in engineered cartilage remains a challenge, as current scaffolds cannot replicate the depth-dependent alignment of collagen and its ECM interactions.

  • Insights gained from cartilage development and its anisotropic organization could inspire novel strategies for achieving long-term cartilage regeneration.

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Fig. 1: Development of knee articular cartilage from embryogenesis to adulthood.
Fig. 2: Collagen fibrillogenesis.
Fig. 3: Proposed mechanism for the guidance of collagen type II fibres in articular cartilage.
Fig. 4: Proteoglycan aggrecan synthesis.
Fig. 5: The main components of articular cartilage extracellular matrix.
Fig. 6: Strategies for guiding collagen in articular cartilage restoration and biofabrication.

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Acknowledgements

A.P.M., M.d.R., K.I. and J.M. would like to acknowledge the support of the Dutch Research Council (NWO), project LS-NeoCarE (NWA.1389.20.192) and the Gravitation Program “Materials Driven Regeneration” (024.003.013). J.M. would like to acknowledge support from the European Research Council (ERC) under the European Union’s Horizon Europe research and innovation programme (Re-COLL: 101142063). F.Z. would like to acknowledge funding from the Deutsche Forschungsgemeinschaft (ZA 561/3-2, project number 407168728) within the research unit FOR2722. D.J.K. would like to acknowledge support from Science Foundation Ireland (22/FFP-A/11042) and the European Research Council (ERC) under the European Union’s Horizon Europe research and innovation programme (4D BOUNDARIES: 101019344). J.M. and D.J.K. would like to acknowledge the European Commission (m2M: 101191729).

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Authors and Affiliations

  1. Regenerative Medicine Center Utrecht, Utrecht, the Netherlands

    Alba Pueyo Moliner, Mylène de Ruijter & Jos Malda

  2. Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands

    Alba Pueyo Moliner, Keita Ito, Mylène de Ruijter & Jos Malda

  3. Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands

    Keita Ito

  4. Department of Trauma Surgery and Orthopedics, Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany

    Frank Zaucke

  5. Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Daniel J. Kelly

  6. Department Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands

    Mylène de Ruijter & Jos Malda

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Contributions

A.P.M. researched data for the article. A.P.M., J.M. and M.d.R. wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Jos Malda.

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Glossary

Anisotropic

Having direction-dependent properties.

Arcade-like structure

A collagen fibre arrangement in articular cartilage whereby fibres curve from the surface to the deep zone, anchoring to the subchondral bone.

Beaded microfibrillar network

A structural arrangement of thin, bead-like fibrils connected in a network.

Fibrillogenesis

The process of collagen fibril formation.

Heterotypic fibres

Collagen fibres composed of more than one type of collagen molecule.

Hypertrophy

The process by which cells undergo significant enlargement owing to volumetric increase and distinct metabolic and molecular changes.

Isotropic

Having uniform properties in all directions.

Joint cavitation

The formation of the joint cavity during embryonic development, separating the joint into two articular surfaces.

Liquid crystallinity

A state of matter with properties between those of a liquid and a solid crystal, characterized by ordered molecular alignment.

Molecular crowding

A high concentration of macromolecules in a confined space that influences molecular interactions and assembly.

Nascent

Newly formed or immature.

Non-reducible crosslinks

A non-reversible chemical bond that permanently stabilizes collagen fibrils.

Nucleator

A molecule or structure that promotes the initiation of fibrillogenesis.

Procollagen

The precursor molecule of collagen that undergoes enzymatic processing to form tropocollagen.

Reducible crosslinks

A reversible chemical bond that stabilizes collagen fibrils.

Resistance to the positive principal strain

The ability of a material to withstand tensile forces along the direction of the highest principal strain.

Split-line orientation pattern

A pattern observed on the surface of cartilage that reflects the underlying collagen fibre alignment.

Suprafibrillar assemblies

Higher-order structures formed by the organization of fibrils into complex networks.

Tidemark

Boundary between the calcified and non-calcified zones of articular cartilage.

Tropocollagen

The basic triple-helical collagen molecule that assembles into fibrils.

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Pueyo Moliner, A., Ito, K., Zaucke, F. et al. Restoring articular cartilage: insights from structure, composition and development. Nat Rev Rheumatol 21, 291–308 (2025). https://doi.org/10.1038/s41584-025-01236-7

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