Review
Enhanced cartilage repair in ‘healer’ mice—New leads in the search for better clinical options for cartilage repair

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Abstract

Adult articular cartilage has a poor capacity to undergo intrinsic repair. Current strategies for the repair of large cartilage defects are generally unsatisfactory because the restored cartilage does not have the same resistance to biomechanical loading as authentic articular cartilage and degrades over time. Recently, an exciting new research direction, focused on intrinsic cartilage regeneration rather than fibrous repair by external means, has emerged. This review explores the new findings in this rapidly moving field as they relate to the clinical goal of restoration of structurally robust, stable and non-fibrous articular cartilage following injury.

Introduction

At its simplest, articular cartilage, located at the ends of long bones and in articulating joints, is a meshwork of highly organized and cross-linked collagen fibrils that immobilize the hydrophilic proteoglycan aggrecan. The molecular properties of these components allow the joint cartilage to resist both compressive and tensile forces associated with locomotion and daily activities. In humans, full-thickness cartilage lesions that penetrate the subchondral bone heal poorly and cartilage lacerations do not heal, probably because of the lack of resident blood vessels, lymphatic vessels, and nerves, and access to reparative cells. Traumatic articular cartilage damage typically leads to a cascade of events that result in further cartilage damage, cartilage erosion and later, osteoarthritis (OA) [1], [2]. To date, clinical options for patients with traumatic cartilage defects remain limited to symptomatic treatment until patients become candidates for total joint replacement. In recent years, treatments that attempt to repair or restore the cartilage lesion have started to be developed to slow or stop the progression towards OA. These include the microfracture technique, osteochondral auto/allografts, autologous chondrocyte implantation, and osteochondral transplant systems. In general, these approaches have provided variable and unpredictable results [3], [4], [5], [6], [7], [8], [9], [10]. The microfracture and related techniques mostly produce fibrocartilage and thus do not offer a long-term solution. Autologous chondrocyte implantation is expensive and technically difficult and the long-term functional properties of the repaired defect have yet to be assessed. Other more experimental approaches that have yet to reach the clinic involve using tissue engineered or artificial scaffolds [11], [12]. While tissue-engineering approaches are promising, they are still some time away from clinical use. Hence, there is a great clinical need for new research directions and novel treatment modalities for the repair of full-thickness cartilage defects. One such approach that has emerged in recent years focuses on the body’s ability to regenerate tissue instead of effecting repair. This process has been studied mostly in invertebrates and amphibians but recent findings of limited epimorphic regeneration in certain strains of mice raises the real possibility of inducing a response to injury that involves authentic tissue regeneration, rather than fibrous repair.

Section snippets

Emerging evidence for mammalian tissue regeneration

Wound repair in the tissues of higher organisms is dominated by a fibroproliferative response where the injured organ is patched (repaired) rather than restored structurally and functionally to its original condition (regenerated). It is important to make the distinction between ‘repair’ and ‘regeneration’. Normal wound repair is a highly dynamic process that involves blood vessel disruption, clotting and the initiation of inflammatory processes [13]. The initial inflammatory stage is

Articular cartilage is capable of regeneration

In 2008, a trio of papers reported enhanced articular cartilage healing in two strains of mice: the MRL/MpJ ‘healer’ mice, described above, and the DBA/1 strain. Since the MRL/MpJ strain has been shown to undergo scarless healing in several tissues, including auricular cartilage following ear lesion, we assessed whether articular cartilage lesions, which normally induce a fibrocartilaginous response, could ‘regenerate’ in the MRL/MpJ strain [52]. Full-thickness trochlear groove lesions that

Mapping the articular cartilage healing trait

It is clear that, although the MRL/MpJ and DBA/1 strains healed better overall compared to the control strains, there were good and poor healers within both the healer and non-healer strains suggesting that genetic variability was influencing the articular cartilage healing trait. This is consistent with earlier studies establishing that enhanced ear wound closure in MRL/MpJ mice is a complex genetic trait involving the interaction of multiple genetic factors [55], [56], [57], [58]. Recent

Progress towards identifying cartilage regeneration-promoting genes

With the assumption that a common set of genes are involved in ear hole closure and articular cartilage regeneration, Rai et al. [66] investigated gene expression differences in ear wound tissue and articular cartilage from the common inbred and recombinant inbred strains described above [63], [64]. A key finding from cluster analysis of the gene expression data was that the strains clustered with their healing ability [63]. One cluster contained the healers (MRL/MpJ, LG/J, LGxSM-6) and the

Several distinct mechanisms appear to promote articular cartilage healing

Genetic, cellular, and metabolic comparisons between MRL/MpJ and non-healer strains have revealed many striking differences in a range of processes, leading to speculation on mechanisms for the enhanced regeneration phenotype. The reader is directed to an excellent review by Heydemann, where these are covered in detail [51]. The discussion here focuses on a subset of possible mechanisms as they relate to articular cartilage healing.

Outlook for cartilage regeneration research

The finding that mammals have retained a higher capacity for cartilage regeneration than previously assumed is an unexpected observation and has stimulated interest in using regenerative medicine to isolate molecular pathways that could promote enhanced tissue repair. The healer mice identified in recent years appear to possess an intrinsic ability to bypass the normal fibrotic ‘repair’ response and, instead, execute a more ‘regenerative’ program of tissue restoration, suggesting that ancient

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