Abstract
The absence of leptin results in contrasting growth pattern of appendicular and axial bone growth in ob/ob mice. Endochondral bone formation is an important procedure of growth plate determining the bone growth, where this procedure is also regulated by estrogen and its receptor (ER) signaling pathway. The present study is undertaken to explore the roles of ERs in regulating the different growth patterns in ob/ob mice. In this study, C57BL/6 female mice were used as wild-type (WT) mice; ob/ob mice and WT mice were age-matched fed, and bone length is analyzed by X-ray plain film at the 12 weeks old. We confirm that ob/ob mice have shorter femoral length and longer spine length than WT mice (p < 0.05). The contrasting expression patterns of chondrocyte proliferation proteins and hypertrophic marker proteins are also observed from the femur and spinal growth plate of ob/ob mice compared with WT mice (p < 0.01). Spearman’s analysis showed that body length (axial and appendicular length) is positively related to the expression level of ERα in growth plate. Three-week-old female ob/ob mice are randomized divided into three groups: 1) ob/ob + ctrl, 2) ob/ob + ERα antagonist (MPP), and 3) ob/ob + ERβ antagonist (PHTPP). Age-matched C57BL/6 mice were also divided into three groups, same as the groups of ob/ob mice. MPP and PHTPP were administered by intraperitoneal injection for 6 weeks. However, the results of X-ray and H&E staining demonstrate that leptin deficiency seems to disturb the regulating effects of ER antagonists on longitudinal bone growth. These findings suggested that region-specific expression of ERα might be associated with contrasting phenotypes of axial and appendicular bone growth in ob/ob mice. However, ER signaling on longitudinal bone growth was blunted by leptin deficiency in ob/ob mice, and the underlying association between ERs and leptin needs to be explored in future work.
Highlights
Leptin, a protein encoded by obese gene, has been shown to have regulative effects on longitudinal bone growth, spongiosa maturation, and bone turnover between cortical and cancellous bones [1]
Additional histological analysis for the proliferative zone and hypertrophic zone of femur growth plate (GP) showed that both zones were decreased in the ob/ob mice compared with WT mice (Figure 2C), while the ratio of hypertrophic/ proliferative zone of femoral GP was higher in ob/ob mice than in WT mice (Figures 2D, E)
The current study provides further evidence for the effects of leptin deficiency on the contrasting phenotypes on axial and appendicular bone growth, in which leptin deficiency results in region-specific expression of ERa at the femoral and vertebral GP in ob/ob female mice
Summary
A protein encoded by obese gene (ob), has been shown to have regulative effects on longitudinal bone growth, spongiosa maturation, and bone turnover between cortical and cancellous bones [1]. Endochondral bone formation is the key procedure for growth plate (GP), in which GP chondrocytes undergo a series of organized procedures including proliferation, maturation, hypertrophic differentiation, and calcification [8,9,10]. These complex and delicate programs of endochondral bone formation are responsible for the skeletal elongation. The integration of estrogen and leptin signaling, which is responsible for contrasting growth patterns in appendicular and axial longitudinal growth via ERs, is still unknown. We hypothesize that leptin deficiency may influence the ER expression in axial and appendicular GP in vivo, contributing to the contrasting phenotypes of skeletal growth in ob/ob mice. We examine the femur and spinal GP using densitometric, histomorphometric, and immunohistochemical techniques to expand our current understanding of how the absence of leptin affects axial and appendicular growth
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