Heritability of articular cartilage regeneration and its association with ear wound healing in mice.

Tissue regeneration is a property generally attributed to organisms other than mammals. For example, hydra and planaria can regenerate their entire bodies from a small fraction of their tissues (1, 2). Similarly, vertebrates including newts and salamanders can regenerate limbs or other structures after amputation (3, 4). In contrast, the regenerative capacity in mammals is extremely limited (5) and is generally confined to shedding and re-growth of antlers in deer (6) and moose (7), and ear-wound closure in rabbits (8). Despite this limited regeneration in adult mammals, supporting evidence suggests that certain mouse strains possess unusual abilities to regenerate/repair tissues even into adulthood. For instance, MRL/MpJ (9–12), and LG/J (11, 13) strains display 2-millimeter through-and-through ear-hole closure within 4-weeks. Articular cartilage is generally thought to have limited regeneration capacity, but there are sporadic reports of full-thickness articular cartilage healing in rats (14), rabbits (15), dogs (16) and horses (17). Spontaneous regeneration of cartilage is possible only when the defect penetrates through the cartilage extending through the subchondral bone to the bone-cavity to presumably access mesenchymal stem cells and recruit them to the site of damage (18, 19). In this case, the newly formed tissue is typically fibrocartilage, which is mechanically weak and degenerates over time (15, 20). In partial-thickness defects no effective repair response occurs (10, 21) and attempts to restore/repair cartilage injuries have met with unpredictable and variable outcomes (22, 23). Lack of self-regeneration in articular cartilage, mainly because of its intrinsic avascularity, contributes to cartilage degeneration, predisposing an individual to the development of osteoarthritis (OA), leading to prosthetic joint replacement and disability (22–24). While it is well-appreciated that OA is widespread, over 50% of individuals are protected from post-traumatic OA despite suffering from cartilage damage (25). The exact cause for this remains unknown and can be attributed to a greater intrinsic ability to regenerate cartilage (26). Our long-term goal is to understand why some people can repair or regenerate cartilage while insult or aging results in degeneration in others. Recently, two mouse strains, MRL/MpJ and DBA/1, were reported to regenerate full-thickness articular cartilage defects in contrast to a failure of healing in age-matched C57BL/6 mice. The regenerated cartilage is hyaline-like in nature and has abundant chondrocytes, an extracellular matrix rich in proteoglycan, persistent types II and VI collagen neo-deposition, and cell proliferation within the repair tissue (10, 21). MRL/MpJ and LG/J, two closely-related mouse strains sharing 75% of their genomes identical-by-descent (2), can completely heal ear-wounds including ear cartilage (9, 13, 27). This raises the possibility that, like MRL/MpJ, LG/J may also heal articular cartilage. To investigate this possibility, we have examined the extent of cartilage regeneration in a set of common inbred strains, including both healers and non-healers, and in a set of recombinant inbred (RI) lines formed from the intercross of the LG/J (healer) and SM/J (non-healer) inbred mouse strains. The conceptual starting point for RI lines is that any differential phenotype will be attributed to a restricted set of genes according to the way they have been inherited from parental strains. It is estimated that 30–75% of the variation in OA is due to genetic differences (28, 29). While OA in humans can be studied using cartilage from donors, usually at the time of total joint replacement, it is impossible to directly investigate cartilage repair in humans. Therefore, we took the approach of investigating cartilage regeneration in genetic mouse models. In this study we aim to (1) investigate heritability for articular cartilage regeneration in common inbred strains and RI lines and (2) to determine the correlation between ear-wound healing and articular cartilage regeneration. We found that cartilage regeneration is indeed a heritable trait in the LG/J by SM/J intercross so that this intercross can be used to dissect the genetic basis of variation in articular cartilage regeneration. Furthermore, a strong genetic correlation between the ability to heal ear-wounds and the ability to regenerate articular cartilage suggests a common underlying mechanism.