PLOD2, a key factor for MRL MSC metabolism and chondroprotective properties

Author:

Bahraoui Sarah1,Tejedor Gautier1,Mausset-Bonnefont Anne-Laure1,Autelitano François2,Jorgensen Christian1,Wei Mingxing3,Djouad Farida4ORCID

Affiliation:

1. INSERM

2. Sanofi-Aventis Recherche et Développement Toulouse-Labège: Evotec France SAS

3. CellVax

4. Inserm U1183

Abstract

Abstract Background: Initially discovered for its ability to regenerate ear holes, the MRL mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained in the adult, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that MSC derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators. Method: To address this hypothesis, we compared the transcriptome of MRL and BL6 MSC and identified several candidate molecules expressed at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate and performed functional in vitro assays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. Using an experimental model for osteoarthritis (OA) induced by collagenase (CiOA), we assessed its contribution to MRL MSC protection from OA. Results: Among the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), coding for the lysyl hydrolase LH2 in charge of post-translational modifications of collagen for its stability and stiffness. PLOD2 is induced by hypoxia-inducible factor 1-alpha (HIF-1a) involved in the regeneration process of adult MRL mice. Plod2 silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, we showed that plod2 silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA. Conclusion: Our results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2.

Publisher

Research Square Platform LLC

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