Effects of Gender on the Intrinsic Biological Potential of Osteoblastic Cells

Oral presentation: Section A

Age and gender associated differences in bone mass among normal individuals are well known clinical events. Changes in the systemic hormonal and cytokine environment contribute significantly to this clinical variation. Levels of estrogens, PTH, leptin, and vitamin D are particularly important [1][2][3]. Contributions of genetic variation are becoming better documented, particularly variation expression of estrogen receptors [4] and low density lipoprotein receptor-related protein 5 (e.g., LRP5) [5]. Epigenetic variation may also contribute to variation in bone mass skeletal metabolism. Changes in the number of osteoblastic stem cells and progenitors as a function of age has been documented in a number of studies [6][7][8]. Gender specific changes in the intrinsic biological performance of osteoblastic stem cells and osteoblastic progenitors are yet another likely source of variation, that is likely to be relevant clinically to skeletal development and homeostasis.

Bone marrow, harvested by aspiration is a rich source of osteoblastic stem cells and progenitors, though osteoblastic progenitors can also be found in periosteum fat and in muscle tissue. Marrow aspirates contains connective tissue progenitor cells (CTPs) which can be induced to express one or more connective tissue phenotypes, including osteoblast in vitro [9][10][11][12][13][14]. Several previous animal studies have suggested that number of bone marrow derived CTPs decrease with aging [15][16]. Clinically, the number of cells and CTPs in bone marrow has been shown to decrease with age in both men and women. Women have been shown to exhibit a greater age related decline in the number of osteoblastic progenitors among marrow cells harvested from iliac crest [6]. Age related changes in the mitotic potential or differentiation of osteoblastic progenitors have also been suggested, regardless of gender [6][8][17][18].

In addition to changes in the number of osteoblastic stem cells and progenitors that are available to support bone healing or remodeling, changes in intrinsic biological potential may also vary systematically with gender. For example, female cells isolated from human bone have been shown to have a lower level of alkaline phosphasphatase stimulation with administration of 1,25-(OH)₂Vit D₃, and a lower basal expression of osteocalcin than male cells [19]. There is also suggestion that male and female mesenchymal cells, osteoblasts and osteocytes may differ with respect to expression of estrogen receptor isoforms, ER-α and ER-β [4]. Gender specific differences at a cellular level have been described in a variety of other tissues, including cardiac fibroblasts [20], vascular smooth muscle cells [21], and spleen cells [22].

A greater level of attention and effort is needed to adequately characterize the intrinsic differences between male and female cells, and the effect that these differences have on skeletal development, repair, and remodeling. These differences are likely to be particularly important to the development and assessment of rational and strategic gender specific therapeutic strategies.

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