High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors.

The MRL/MpJ mice have demonstrated an enhanced tissue regeneration capacity for various tissues. In the present study, we systematically characterized bone microarchitecture and found that MRL/MpJ mice exhibit higher bone microarchitecture and strength compared to both C57BL/10J and C57BL/6J WT mice at 2, 4, and 10 months of age. The higher bone mass in MRL/MpJ mice was correlated to increased osteoblasts, decreased osteoclasts, higher cell proliferation, and bone formation, and enhanced pSMAD5 signaling earlier during postnatal development (2-month old) in the spine trabecular bone, and lower bone resorption rate at later age. Furthermore, these mice exhibit accelerated fracture healing via enhanced pSMAD5, pAKT and p-P38MAPK pathways compared to control groups. Moreover, MRL/MpJ mice demonstrated resistance to ovariectomy-induced bone loss as evidenced by maintaining higher bone volume/tissue volume (BV/TV) and lower percentage of bone loss later after ovariectomy. The consistently higher serum IGF1 level and lower RANKL level in MRL/MpJ mice may contribute to the maintenance of high bone mass in uninjured and injured bone. In conclusion, our results indicate that enhanced pSMAD5, pAKT, and p-P38MAPK signaling, higher serum IGF-1, and lower RANKL level contribute to the higher bone microarchitecture and strength, accelerated healing, and resistance to osteoporosis in MRL/MpJ mice.