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Gender differences in tibial fractures healing in normal and muscular dystrophic mice.

ABSTRACT: Duchenne muscular dystrophy (DMD) patients have a high fracture risk and poor fracture healing. The dystrophin-/- (mdx) mouse is a murine model of DMD and exhibits delayed bone fracture healing. Since our research team has shown that adult stem cells, such as muscle-derived stem cells, display a gender difference in their osteogenic potential with the male cells being more osteogenic, we hypothesize that a potential gender differences may exist during bone healing in normal and mdx mice. To test this hypothesis, wild-type (WT) and mdx mice underwent tibial fracture surgery and microCT live scanning biweekly. The mice were sacrificed at 6 weeks post-surgery and the calluses were collected for histological analysis. To further investigate the mechanism, another two sets of mice were sacrificed at 10 days after fracture for RNA extraction and gene expression analysis and histology. MicroCT results showed, at 6 weeks post- surgery, the calluses were larger but showed less remodeling in both normal and mdx male mice when compared to females, at the same time point. However, females had higher callus bone volume density and an increase in osteoclast (OCs) number. At 10 days after fracture surgery, male mice had formed larger calluses, whereas females formed well-remodeled calluses with more osteoblasts and a greater bone area for both WT and mdx mice. Higher IGF-1 expression was observed in male mdx mice when compared to their female counterparts, whereas female WT mice had higher BMP-9 expression when compared to WT males. In conclusion, male mice formed larger bone calluses than females during tibial fracture healing for both WT and mdx mice. This may be attributed to higher IGF-1 expression, activation of Wnt/?-catennin signaling pathway and greater OB numbers during callus formation. Female mice achieved better bone remodeling in the regenerated bone with higher bone quality due to increased OC numbers that promote faster remodeling of the fracture calluses, and higher BMP-9 expression levels. Therefore, gender is one of many factors that need to be considered for both animal and human bone research.

SUBMITTER: Deng Z

PROVIDER: S-EPMC7344076 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Gender differences in tibial fractures healing in normal and muscular dystrophic mice.

Deng Zhenhan Z Gao Xueqin X Sun Xuying X Cui Yan Y Amra Sarah S Huard Johnny J

American journal of translational research 20200615 6

Duchenne muscular dystrophy (DMD) patients have a high fracture risk and poor fracture healing. The dystrophin<sup>-/-</sup> (<i>mdx</i>) mouse is a murine model of DMD and exhibits delayed bone fracture healing. Since our research team has shown that adult stem cells, such as muscle-derived stem cells, display a gender difference in their osteogenic potential with the male cells being more osteogenic, we hypothesize that a potential gender differences may exist during bone healing in normal and ...[more]

PMID: 32655796

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Project description:PurposeTo examine the condition and triggers of stress fractures of the lateral tibial plateau (LTP) similar to type III lateral hinge fractures (LHFs) after open wedge high tibial osteotomy (OWHTO).MethodsOWHTO was performed in 118 knees. They were examined for LHFs by computed tomography (CT). Patients were divided into the stress fracture group (Group SF) if they showed fracture lines on CT performed after starting weight-bearing walking and the normal group (Group N) for others.ResultsThe mean age was significantly older in Group SF (P = 0.022). Preoperatively, Group SF showed a significantly higher tibio-femoral angle (TFA, P = 0.014). No significant differences were observed in TFA and weight-bearing line ratio after surgery. Correction angle was significantly higher in the SF group. And all of the SF were more than 13 degrees. There was no significant difference in LHF incidence between groups, whereas stress fracture incidence differed significantly for each type of LHF (chi-squared test, P = 0.0001): 14.6% of type I cases, 100% of type II cases, 0% of type III cases, and 6.1% of those without LHF.DiscussionThe load on the LTP is assumed to act as a shearing force in type II fractures, which may contribute greatly to stress fractures. In type III, stress fractures may not occur because of the load dispersed at the fracture part. The stress fracture site is similar to type III LHF, and this kind of fracture is thought to be a delayed type III because it occurs after patients start weight-bearing walking. Moreover, they are observed in type I cases with a stable hinge and in 6% of cases without LHF. This study showed that high varus knees corrected with a large correction angle may develop stress fractures. OWHTO requires attention to stress fractures of the LTP, which can be regarded as delayed type III, in those developing LHFs postoperatively or having a high varus knee preoperatively.ConclusionThese results indicated the possibility of stress fracture in LTP during weight-bearing exercise after OWHTO, which was regarded as a delayed type III fracture. The results showed that Correction angle was more than 13 degrees, and lateral hinge fracture type II of the Takeuchi classification was an inducement of this stress fracture.Level of evidenceLevel IV.

Project description:Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the alpha 7 beta 1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha 7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha 7 beta 1 integrin can compensate for the absence of dystrophin, we expressed the rat alpha 7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering alpha 7 beta 1 integrin-mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr(-/-) mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the alpha 7 beta 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

Dataset Information

Gender differences in tibial fractures healing in normal and muscular dystrophic mice.

Publications

Gender differences in tibial fractures healing in normal and muscular dystrophic mice.

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