Agrin mediates chondrocyte homeostasis and requires both LRP4 and a-dystroglycan to enhance cartilage formation in vitro and in vivo

Suzanne Eldridge, Giovanna Nalesso, Habib Ismail, Karin Vicente-Greco, Panos Kabouridis, Manoj Ramachandran, Andreas Niemeier, Joachim Herz, Costantino Pitzalis, Mauro Perretti, Francesco Dell'Accio

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Objectives Osteoarthritis (OA) is a leading cause of disability for which there is no cure. The identification of molecules supporting cartilage homeostasis and regeneration is therefore a major pursuit in musculoskeletal medicine. Agrin is a heparan sulfate proteoglycan which, through binding to low-density lipoprotein receptor-related protein 4 (LRP4), is required for neuromuscular synapse formation. In other tissues, it connects the cytoskeleton to the basement membrane through binding to a-dystroglycan. Prompted by an unexpected expression pattern, we investigated the role and receptor usage of agrin in cartilage. Methods Agrin expression pattern was investigated in human osteoarthritic cartilage and following destabilisation of the medial meniscus in mice. Extracellular matrix (ECM) formation and chondrocyte differentiation was studied in gain and loss of function experiments in vitro in three-dimensional cultures and gain of function in vivo, using an ectopic cartilage formation assay in nude mice. Receptor usage was investigated by disrupting LRP4 and a-dystroglycan by siRNA and blocking antibodies respectively. Results Agrin was detected in normal cartilage but was progressively lost in OA. In vitro, agrin knockdown resulted in reduced glycosaminoglycan content, downregulation of the cartilage transcription factor SOX9 and other cartilage-specific ECM molecules. Conversely, exogenous agrin supported cartilage differentiation in vitro and ectopic cartilage formation in vivo. In the context of cartilage differentiation, agrin used an unusual receptor repertoire requiring both LRP4 and a-dystroglycan. Conclusions We have discovered that agrin strongly promotes chondrocyte differentiation and cartilage formation in vivo. Our results identify agrin as a novel potent anabolic growth factor with strong therapeutic potential in cartilage regeneration.

Original languageEnglish (US)
JournalAnnals of the Rheumatic Diseases
DOIs
StateAccepted/In press - Aug 19 2015

Fingerprint

Agrin
Dystroglycans
Lipoprotein Receptors
Cartilage
Chondrocytes
Homeostasis
Proteins
Osteoarthritis
Extracellular Matrix
SOX9 Transcription Factor
In Vitro Techniques
Regeneration
LDL-Receptor Related Proteins
Tibial Meniscus
Heparan Sulfate Proteoglycans
Molecules
Blocking Antibodies
LDL Receptors
Glycosaminoglycans
Cytoskeleton

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Agrin mediates chondrocyte homeostasis and requires both LRP4 and a-dystroglycan to enhance cartilage formation in vitro and in vivo. / Eldridge, Suzanne; Nalesso, Giovanna; Ismail, Habib; Vicente-Greco, Karin; Kabouridis, Panos; Ramachandran, Manoj; Niemeier, Andreas; Herz, Joachim; Pitzalis, Costantino; Perretti, Mauro; Dell'Accio, Francesco.

In: Annals of the Rheumatic Diseases, 19.08.2015.

Research output: Contribution to journalArticle

Eldridge, S, Nalesso, G, Ismail, H, Vicente-Greco, K, Kabouridis, P, Ramachandran, M, Niemeier, A, Herz, J, Pitzalis, C, Perretti, M & Dell'Accio, F 2015, 'Agrin mediates chondrocyte homeostasis and requires both LRP4 and a-dystroglycan to enhance cartilage formation in vitro and in vivo', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2015-207316
Eldridge, Suzanne ; Nalesso, Giovanna ; Ismail, Habib ; Vicente-Greco, Karin ; Kabouridis, Panos ; Ramachandran, Manoj ; Niemeier, Andreas ; Herz, Joachim ; Pitzalis, Costantino ; Perretti, Mauro ; Dell'Accio, Francesco. / Agrin mediates chondrocyte homeostasis and requires both LRP4 and a-dystroglycan to enhance cartilage formation in vitro and in vivo. In: Annals of the Rheumatic Diseases. 2015.
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AU - Vicente-Greco, Karin

AU - Kabouridis, Panos

AU - Ramachandran, Manoj

AU - Niemeier, Andreas

AU - Herz, Joachim

AU - Pitzalis, Costantino

AU - Perretti, Mauro

AU - Dell'Accio, Francesco

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