Features of bone remodeling and osteoreparation processes in modeling femoral fracture in genetically modified mice with impaired enzymatic regulation of steroid hormone metabolism
Authors: Korokin Mikhail V. , Gudyrev Oleg S. , Pokrovskaya Tatiana G. , Danilenko Lyudmila M. , Zhernakova Nina I. , Avtina Tatyana V. , Parshina Alina V. , Pribylov Sergey A. , Lebedev Petr R. , Kochkarov Alim A. , Kuzubova Elеna V. , Radchenko Alexandra I. , Koklin Ivan S. , Taran Eduard I. 
Published: March 2024

Introduction: The aim of this study was to evaluate the processes of bone remodeling and osteoreparation in modeling femoral fracture in mice with zero expression of 11β-HSD2 (11β-HSD2-/-) or both 11β-HSD2 and apolipoprotein e (11β-HSD2-/-/ApoE-/-).

Materials and Methods: The experimental study was conducted on 60 male mice weighing 24-30 g. The study used male mice that lacked the expression of 11β-HSD2 (knockout mice with the Hsd2-/- genotype) and male mice that lacked the expression of 11β-HSD2 and apolipoprotein E (double knockout mice with the Hsd2-/-/ApoE-/- genotype). The control group includes wild type C57bl/6 animals. Modeling of a fracture of the proximal metaphysis of the femur was performed in animals at the age of 6 months using a closed technique. Fracture fusion and bone remodeling and osteoreparation processes were evaluated 6 weeks after fracture modeling.

Results and Discussion: It has been shown that a violation of the regulation of steroid hormone metabolism in groups of animals with the Hsd2-/- and Hsd2-/-/ApoE-/- genotypes leads to an increase in the number of ungrown fractures by 3 and 3.5 times, respectively, in comparison with wild-type animals. It was found that the microcirculation level of the proximal metaphysis of the left femur in the area of the formed bone callus in the group of animals with the genotype 11β-HSD2-/- significantly decreased from 92.075±4.33 perfusion units (PE) in the group of wild-type animals to 82.67±3.54 PE (p=0.0002) in the group of animals with the genotype HSD2-/- and up to 75.85±5.64 (p<0.0001) in the group of mice with the Hsd2-/-/ApoE-/- genotype. When calculating the coefficient of endothelial dysfunction, an increase in the coefficient of endothelial dysfunction was found from 1.297±0.19 in intact animals to 2.115±0.45 (p<0.00001) in the group of mice with the Hsd2-/- genotype and to 2.41±0.04 (p<0.00001) in the group of mice with the Hsd2-/-/ApoE-/- genotype. In animals with impaired cortisol metabolism, there was a slowdown in the formation of bone tissue in the fracture area, bone trabeculae had a smaller width, large amounts of fibrous and connective tissue were observed in the lumen between bone fragments, and an increase in intertrabecular spaces was noted

Conclusion: The close relationship between the metabolism of 11β-HSD2 and NO, confirmed in this study, can be considered as a promising pharmacotherapeutic target. It is obvious that approaches to changing the activity of 11β-HSD have significant therapeutic potential in the treatment of osteoporosis, bone remodeling disorders and osteoreparation in fractures against the background of formed osteoporotic changes in the violation of steroid hormone metabolism.