Regular articleEstrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading
Introduction
The primary function of the bones is to bear the muscle contraction- and gravity-induced mechanical forces exerted on them without breaking, consequently enabling efficient locomotion of the body [1], [2]. To successfully carry out this locomotive function, bones are believed to have a loading-driven feedback system which, homologous to a thermostat controlling the temperature inside a house, senses the incident mechanical strain within the loaded bones and subsequently removes bone tissue from sites where the loading is marginal and forms new bone tissue at sites subjected to increased loading in order to provide each bone with the mechanically appropriate size, shape, and architecture [3], [4], [5], [6], [7].
Estrogen, the predominant female sex hormone, has commonly been considered the most important nonmechanical (endocrine) regulator of bone metabolism, taking part in both the accretion of bone mass in adolescence and the loss of bone in senescence [8], [9]. The actions of estrogen have also been linked to the mechanical control of bone homeostasis [10], [11], [12], [13], [14]. Somewhat contradictory to the above-summarized fundamental principle of the skeleton’s adaptation to mechanical loading, the bone loss due to estrogen deficiency continues over a prolonged interval without anticipated compensatory response to increasing mechanical strain experienced by the surviving bone. Thus, it has been postulated that estrogen deficiency actually increases the threshold at which bone cells respond to mechanical strain [3], [11], [12]. In fact, it was recently proposed that postmenopausal osteoporosis per se would be a failure of the bone’s adaptation to functional loading [10].
Although estrogen is the predominant female sex hormone, some believe that estrogen actually is the major biologically active bone steroid in males, too [15], [16], [17]. Recent data also suggest that in both sexes the strain-related proliferation of osteoblasts, the bone-forming cells of the skeleton, is mediated at least in part through a common pathway, the estrogen receptor [18]. Notwithstanding this biological finding, there is some indirect evidence, based on the side-to-side differences of male and female tennis players, that the male skeleton appears clearly more responsive to similar mechanical loading than the female skeleton [19], [20]. The credibility of the cross-sectional data is, however, subject to differences in intensity and frequency of incident loading, to genetic variability, and to many other confounding factors between the given groups of male and female tennis players.
In the light of the above, the initial objective of this study was to evaluate whether there is any sex-related difference in skeletal responsiveness to mechanical loading (treadmill running) between both growing (experiment 1) and mature (experiment 2) female and male rats. As an extension to the findings of the first two experiments, a third experiment (experiment 3) was carried out to assess the notion that the skeletal effects of estrogen would be coupled with the mechanical loading-induced regulation of bone integrity [10], [11], [12] by comparing the skeletal responsiveness of sham-operated and ovariectomized female rats.
Section snippets
Animals
All experiments were approved by the Ethics Committee for Animal Experiments of the University of Tampere. For determination of the effect of sex on the osteogenic sensitivity of bones to loading (experiments 1 and 2), littermates of 50 (25 male and 25 female) 5-week-old and 50 (25 male and 25 female) 33-week-old rats of the Sprague–Dawley strain were used. Rats of both sexes were randomly assigned into exercise (n = 15 in each group) or control (n = 10 in each group) groups and then subjected
Results
The gross characteristics of the animals used in experiments 1–3 are given in Table 2, Table 3, Table 4. As the skeleton shows the most pronounced response to loading during the period of rapid skeletal growth [20], we subjected the 5-week-old littermates of rats of both sexes to an identical, progressive training regimen over virtually the entire period of rapid skeletal growth. Consistent with the existing literature [31], [32], [33], [34], a substantial exercise-induced retardation of the
Discussion
Our first experiment, which assessed whether there is a gender-related difference in the skeletal responsiveness to mechanical loading in growing rats, demonstrated that female bones have both a clearly higher bone density relative to the demands placed on the skeleton (muscle contraction-induced loading) and a significantly less prominent adaptive response to increased loading in comparison to males. These data not only show that the skeleton of growing male rat is clearly more responsive to
Acknowledgements
We thank Mrs. Elina Selkälä and Mrs. Minna Vanhala for excellent technical assistance. Gideon A. Rodan, M.D., Ph.D., and Clinton T. Rubin, Ph.D., are acknowledged for their critical reading and helpful comments on the manuscript. This study was supported by grants from the Research Council for Physical Education and Sports, Ministry of Education, the Medical Research Fund of Tampere University Hospital, the Research and Science Foundation of Farmos, and the Maud Kuistila Research Foundation.
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