CCL21/CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults

Abstract

Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the chemokine receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.

Evaluation of CCL21 role in post-knee injury inflammation and early cartilage degeneration

“…Recent studies by Joutoku et al [ 24 ], using a different animal model showed that local administration of CCL21 to adult rabbits at the knee joints can enhance cartilage repair post osteochondral defect. In Joutoku et al [ 24 ] studies, the experimental defect affected both articular cartilage and osteochondral bone and was deep enough to reach bone marrow [ 24 ]. This allowed the infiltration of mesenchymal stem cells from bone marrow to the injured knee joints for cartilage regeneration.…”

Understanding cartilage protection in OA and injury: a spectrum of possibilities

“…Interestingly, juvenile mice deficient in CCR7 displayed significantly impaired cartilage healing postinjury (longitudinal full-thickness cartilage injury in the trochlear groove) compared to wild-type controls, while adult CCR7-deficient mice developed similar fibrocartilaginous tissue as controls in response to injury. Moreover, exogenous delivery of CCL21 ligand, whose transient expression had been identified at the injury site in juvenile mice, led to enhanced healing in adult rabbit after osteochondral defects [18]. Collectively, these findings suggest that this signaling pathway could be a promising target for the enhancement of adult tissue regeneration.…”

“…Yet, the biological and molecular mechanisms responsible for enhanced regenerative competence at a younger age remains poorly understood. Joutoku et al have recently studied the involvement of chemokines, namely the CCL21/CCR7 axis, in regulating cartilage regeneration at a younger age [18]. Interestingly, juvenile mice deficient in CCR7 displayed significantly impaired cartilage healing postinjury (longitudinal full-thickness cartilage injury in the trochlear groove) compared to wild-type controls, while adult CCR7-deficient mice developed similar fibrocartilaginous tissue as controls in response to injury.…”

“…Direct cartilage injury is commonly used to study the tissue regenerative potential by producing a partial or a FTCD, focally or longitudinally in the trochlear groove, that can reach into the subchondral bone (Table 1) [18,44,90]. These models help examine the effect of genetic manipulations and exogenously delivered treatments, such as cell therapy and tissue-engineered constructs, on cartilage regeneration.…”

“…For instance, spontaneous and trauma-induced cartilage injuries appear to differ in terms of molecular signatures and responses to interventions [17], likely due to divergent mechanisms of disease pathogenesis. Also, age and genetic/epigenetic traits may influence the regenerative competence of animals, thus appearing as confounding factors in cartilage-related studies [17,18].…”