ReviewEnhanced cartilage repair in ‘healer’ mice—New leads in the search for better clinical options for cartilage repair
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
References (97)
Articular cartilage repair: are the intrinsic biological constraints undermining this process insuperable
Osteoarthr. Cartil.
(1999)Articular cartilage repair: basic science and clinical progress: a review of the current status and prospects
Osteoarthr. Cartil.
(2002)- et al.
Treatment algorithm for osteochondral injuries of the knee
Clin. Sports Med.
(2001) - et al.
Articular cartilage. Anatomy, injury, and repair
Clin. Podiatr. Med. Surg.
(2001) Abandoning microfracture of the knee: has the time come
Arthroscopy
(2015)- et al.
The clinical status of cartilage tissue regeneration in humans
Osteoarthr. Cartil.
(2013) - et al.
Regeneration across metazoan phylogeny: lessons from model organisms
J. Genet. Genomics
(2015) - et al.
A new in vivo model for testing cartilage grafts and biomaterials: the ‘rabbit pinna punch-hole' model
Biomaterials
(2001) Keratocyte and fibroblast phenotypes in the repairing cornea
Prog. Retin. Eye Res.
(1999)- et al.
A new murine model for mammalian wound repair and regeneration
Clin. Immunol. Immunopathol.
(1998)
The regenerating mouse ear
Semin. Cell Dev. Biol.
The scarless heart
Semin. Cell Dev. Biol.
response to injury in the MRL/MpJ mouse
Neuroscience
The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia
Metabolism
Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling
Cardiovasc. Diabetol.
Evidence for articular cartilage regeneration in MRL/MpJ mice
Osteoarthr. Cartil.
A novel in vivo murine model of cartilage regeneration. Age and strain-dependent outcome after joint surface injury
Osteoarthr. Cartil.
Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice
Osteoarthr. Cartil.
Regeneration of articular cartilage in healer and non-healer mice
Matrix Biol.
Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration
Cell
Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair
Cytokine
Diminished interleukin-8 (IL-8) production in the fetal wound healing response
J. Surg. Res.
Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse
Clin. Immunol.
Wound healing in the PU.1 null mouse—tissue repair is not dependent on inflammatory cells
Curr. Biol.
Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vivo
Matrix Biol.
Articular cartilage: composition, structure, response to injury, and methods of facilitating repair
Current treatment options for the restoration of articular cartilage
Am. J. Knee Surg.
Autologous chondrocyte implantation
Am. J. Knee Surg.
Cartilage substitutes: overview of basic science and treatment options
J. Am. Acad. Orthop. Surg.
Cartilage regeneration using principles of tissue engineering
Clin. Orthop. Relat. Res.
Autologous mesenchymal progenitor cells in articular cartilage repair
Clin. Orthop. Relat. Res.
Wound healing—aiming for perfect skin regeneration
Science
Cutaneous wound healing
N. Engl. J. Med
Old questions, new tools, and some answers to the mystery of fin regeneration
Dev. Dyn.
Limb regeneration
Wiley Interdiscip. Rev. Dev. Biol.
Appendage regeneration in adult vertebrates and implications for regenerative medicine
Science
Deer antlers: a zoological curiosity or the key to understanding organ regeneration in mammals
J. Anat.
Skin shedding and tissue regeneration in African spiny mice (Acomys)
Nature
Regeneration or scarring: an immunologic perspective
Dev. Dyn.
Liver regeneration
Science
Self-renewal and expansion of single transplanted muscle stem cells
Nature
Autoimmunity and lymphoproliferation: induction by mutant gene lpr, and acceleration by a male-associated factor in strain BXSB mice
Genetic loci that regulate healing and regeneration in LG/J and SM/J mice
Mamm. Genome
Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line
Heredity (Edinb.)
Accelerated wound healing of alkali-burned corneas in MRL mice is associated with a reduced inflammatory signature
Invest. Ophthalmol. Vis. Sci.
Heart regeneration in adult MRL mice
Proc. Natl. Acad. Sci. U. S. A.
Reparative myocardial mechanisms in adult C57BL/6 and MRL mice following injury
Physiol. Genomics
The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair
Proc. Natl. Acad. Sci. U. S. A.
Cited by (11)
Deciphering postnatal limb development at single-cell resolution
2023, iScienceCitation Excerpt :By contrast, the juvenile articular cartilage was verified possessing potent self-repair potential.99 In addition, the super-healing MRL mouse strain had a remarkable healing response of damaged cartilage with more abundant chondrocytes and a richer extracellular matrix compared with non-healer strains.107,108 And genes activating cell proliferation were discovered highly expressed in the super-healing mouse strains, which was correlated with the enhanced articular cartilage self-repair.108,109
Earlier proteoglycan turnover promotes higher efficiency matrix remodeling in MRL/MpJ tendons
2023, Journal of Orthopaedic ResearchMRL/MpJ Mice Resist to Age-Related and Long-Term Ovariectomy-Induced Bone Loss: Implications for Bone Regeneration and Repair
2023, International Journal of Molecular SciencesAnti-inflammatory therapeutic approaches to prevent or delay post-traumatic osteoarthritis (Ptoa) of the knee joint with a focus on sustained delivery approaches
2021, International Journal of Molecular Sciences