Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine.

We showed that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP-2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP-2 expression was retained in adult articular cartilage.

A Mouse Model of Acute Cartilage Injury and Repair.

Chondral defects are common and disabling. The development of pharmacological approaches for cartilage repair requires the availability of in vivo models which are amenable for gain and loss of function and ideally to genetic modification. In this chapter, we describe a method to induce full-thickness cartilage defects which, in young DBA/1 mice, heal spontaneously, but fail to heal in C57BL/6 mice of the same age or in aged DBA/1 mice.

In vivo potency assay for the screening of bioactive molecules on cartilage formation.

Cartilage regeneration is a priority in medicine for the treatment of osteoarthritis and isolated cartilage defects. Several molecules with potential for cartilage regeneration are under investigation. Unfortunately, in vitro chondrogenesis assays do not always predict the stability of the newly formed cartilage in vivo.

WNT3A-loaded exosomes enable cartilage repair.

Cartilage defects repair poorly. Recent genetic studies suggest that WNT3a may contribute to cartilage regeneration, however the dense, avascular cartilage extracellular matrix limits its penetration and signalling to chondrocytes. Extracellular vesicles actively penetrate intact cartilage.

Calcium calmodulin kinase II activity is required for cartilage homeostasis in osteoarthritis.

WNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been associated with the onset of different diseases. Here we investigated the role of the WNT/Calcium Calmodulin Kinase II (CaMKII) pathway in osteoarthritis.

ROR2 blockade as a therapy for osteoarthritis.

Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase-like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling.

Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis.

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface.

Lessons from joint development for cartilage repair in the clinic.

More than 250 years ago, William Hunter stated that when cartilage is destroyed it never recovers. In the last 20 years, the understanding of the mechanisms that lead to joint formation and the knowledge that some of these mechanisms are reactivated in the homeostatic responses of cartilage to injury has offered an unprecedented therapeutic opportunity to achieve cartilage regeneration. Very large investments in ambitious clinical trials are finally revealing that, although we do not have perfect medicines yet, disease modification is a feasible possibility for human osteoarthritis.

WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis.

Objective: Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.

Cellular and molecular mechanisms of cartilage damage and repair.

Cartilage breakdown is the disabling outcome of rheumatic diseases, whether prevalently inflammatory such as rheumatoid arthritis or prevalently mechanical such as osteoarthritis (OA). Despite the differences between immune-mediated arthritides and OA, common mechanisms drive cartilage breakdown. Inflammation, chondrocyte phenotype and homeostatic mechanisms have recently been the focus of research and will be summarised in this review.