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Joint regeneration in newts? Yes, they can!
  1. M Geyer,
  2. T Borchardt,
  3. F Müller-Schrobsdorff,
  4. C Schreiyäck,
  5. C Müller,
  6. A Wietelmann,
  7. C Fiehn,
  8. U Müller-Ladner,
  9. R Dinser
  1. Kerckhoff-Klinik, Department of Rheumatology and Clinical Immunology, Bad Nauheim, Germany

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Introduction

Osteoarthritis causes pain and loss of function of affected joints. To date, no causative treatment is available and endogenous regeneration of damaged mammalian joint structures appears impossible. Since amphibians are able to regenerate whole limbs, we hypothesised that they might be able to repair joints after local joint damage.

Methods

Knee joints of adult newts (Notophthalmus viridescens) were injected with collagenase. The clinical and histological courses were analysed. A parallel in vivo documentation using the same animals was assessed by MRI. Relevant molecular factors possibly involved were analysed by immunohistochemistry as well as by real-time PCR using total RNA from whole joints dissected at different time points after injection.

Results

Both clinically and histologically, there was a definite articular cartilage injury of treated versus untreated joints. The clinical signs of the animals increased over the first 6 days and then ameliorated continuously. After 10 weeks, most of the joints appeared clinically normal. Histology confirmed initial joint luxation and showed a decrease in the proteoglycan content and cartilage volume. Afterwards, new formation of the respective joint compartments could be observed, leading to morphologically intact and functionally operative joints. Moreover, regeneration was also seen in vivo by repeated MRI of animals during their disease course. RT-PCR analysis showed differential expressions of SOX9, COL2A1 and BMP2/4 which were more abundant in treated samples and increased over time. Homogenous expression over time, but varying between treated joints and controls, was found for matrix metalloproteinase 9 (MMP-9) and tissue inhibitors of MMP-1, both of which were upregulated after injury. Expression of COL1A2, CTGF and GAS6 was equal between treated and untreated knee joints with no differences over time. Of note, staining of the blastemal marker 22/18 revealed a minor role for the formation of a regeneration blastema, as is the case in complete limb regeneration.

Conclusion Procedures leading to osteoarthritis in murine models cause significant joint damage in newts. In contrast to mammalian joints, newts are able to repair joint damage and to regenerate a completely functional joint. Interestingly, there does not seem to be a need for a repetition of embryological mechanisms in this type of regeneration.

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