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Endocrine Research Unit College of Medicine Mayo Clinic Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Dr. Sundeep Khosla, Endocrine Research Unit, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: khosla.sundeep{at}mayo.edu.
Males (human or mouse) have bigger bones than females, but there is more to differences between the male and female skeleton than just size. Studies using transiliac bone biopsies (1) and three-dimensional high-resolution peripheral quantitative computed tomography (2) have clearly demonstrated that trabecular structure also differs between the sexes. Males have thicker trabeculae than females and, with aging, lose bone on the basis of thinning of these trabeculae, rather than the complete loss of trabeculae, as occurs in females (1, 2). Thus, whereas studies to date have focused largely on explaining why males have bigger bones than females, as our tools to assess trabecular microstructure become more sophisticated, there is growing interest in trying to understand why males may be different from females not just in bone size but also in bone structure.
It is in this context that the study by DeMambro et al. (3) in this issue is of particular interest. The authors provide a detailed analysis of the skeletal phenotype of male and female IGF binding protein (IGFBP)-2 knockout (IGFBP-2–/–) mice, and whereas their original hypothesis was that IGFBP-2 regulated bone turnover (a plausible notion, based on previous work discussed below), the somewhat unexpected finding was that loss of IGFBP-2 had markedly different consequences for trabecular microstructure in males vs. females. Although the story would have been much simpler if male and female IGFBP-2–/– mice had similar skeletal phenotypes relative to their wild-type (+/+) gender mates, unexpected findings such as those in this study sometimes provide a much more fundamental understanding of biology than had the study actually worked as hypothesized.
Before discussing the study, perhaps it is important to pause and explain why it was worthwhile to examine the skeletons of IGFBP-2–/– mice in the first place. For most of us not particularly enamored by the complexities of the IGF system (two IGFs, six binding proteins, some inhibitory, some stimulatory, each being regulated differently in different tissues), studying the bones of mice with deletion of perhaps one of the more obscure binding proteins (BP-2) might not seem like a useful exercise. Indeed, IGFBP-2 might have remained obscure as far as bone is concerned were it not for the observation some time ago that patients with the rare syndrome of hepatitis C-associated osteosclerosis (HCAO), who have dramatic increases in bone formation and bone mass as adults, also have elevated IGFBP-2 levels along with increases in the IGF-II precursor, IGF-IIE (4). Further analysis of sera from these patients, combined with in vitro (4) and subsequent in vivo studies in rodents (5) demonstrated that IGFBP-2, which binds IGF-IIE, IGF-II, and IGF-I, may serve to target IGFs to bone, leading to the observed stimulation of bone formation in patients with HCAO. The impetus for the studies in these patients came, in turn, from previous work by one of the coauthors (D. R. Clemmons) of the paper by DeMambro et al. (3) demonstrating that the IGF/IGFBP-2 complex had a marked affinity for extracellular matrices containing glycosaminoglycans (6), which are abundant in the bone matrix. Thus, the rationale for studying mice with deletion of IGFBP-2 was certainly credible: loss of IGFBP-2 would lead to impaired targeting or retention of IGFs in bone, in turn resulting in a reduction in bone mass.
As is often the case, the hypothesis of the study was only partially correct. IGFBP-2–/– males, but not females, had reduced trabecular bone volume and thickness, compared with their +/+ gender mates. Whereas at first blush this complexity may be troubling, closer examination of the data in the manuscript reveals something potentially very interesting. Figure 1
shows the key findings of the paper, with the data expressed relative to +/+ females, to highlight the differences between circulating IGFBP-2 levels in the various groups and the impact of loss of IGFBP-2 on gender differences in the main trabecular structural variable that differs most between males and females, trabecular thickness (1, 2). As is evident (Fig. 1A), +/+ males had 66% higher circulating IGFBP-2 levels, compared with females, and deletion of IGFBP-2 led to equivalent (in this case, nonexistent) IGFBP-2 levels in the two sexes. The impact of this on trabecular thickness at 8 wk, when the mouse skeleton is maturing, was remarkable: whereas +/+ males had 24% thicker trabeculae than +/+ females, eliminating the difference in circulating (and presumably, tissue) levels of IGFBP-2 eliminated the gender difference in trabecular thickness (Fig. 1B). This is a remarkable and unexpected finding. Here is a relatively obscure IGFBP appearing to be entirely responsible for gender differences in trabecular structure. Could this really be true?
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provides a working model of how IGFBP-2 may do this. Consistent with the higher circulating IGFBP-2 levels in males, compared with females, noted in this paper (3), studies in prostate cells (in which the role of IGFBP-2 as a mediator of tumor progression has been extensively studied) have found that androgens stimulate IGFBP-2 production (7). Thus, although data on regulation of IGFBP-2 in bone cells are lacking, a plausible assumption is that the surge of androgens in males during puberty would be expected to increase circulating and tissue levels of IGFBP-2 relative to females. Based on the previous work from the laboratory of Clemmons and colleagues (6) and the findings in HCAO patients (4), this would lead to complex formation of IGFBP-2 with the IGFs (I and II), resulting in increased targeting of systemically circulating IGFs and/or retention of locally produced IGFs in the bone matrix, stimulating bone formation during growth, and leading to the greater trabecular thickness in males, compared with females. The authors, however, also suggest another possible pathway by which the increase in IGFBP-2 might alter trabecular structure. As shown in Fig. 2, the authors demonstrate that IGFBP-2 suppresses expression of the phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which interferes with IGF and other growth factor signaling by dephosphorylating phosphatidylinositol-3,4,5-trisphosphate (8). Whereas the complexities of PTEN are beyond the scope of this discussion, the key point is that IGFBP-2, perhaps by virtue of binding an integrin receptor (9), suppresses PTEN phosphatase activity, with the net effect being an enhancement of IGF (and other growth factor) signaling. As shown in Fig. 2, this would also lead to an increase in bone formation and trabecular thickness. Consistent with this, previous work from the laboratory of Clemens (distinct from Clemmons) and colleagues (10) has shown that deletion of PTEN specifically in osteoblasts leads to thicker trabeculae in mice.
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In summary, the carefully done study of DeMambro et al. (3) is an excellent example of where being partially right is sometimes better than being entirely right. Once the disappointment of being wrong (or only partially right) subsides, meticulous science generally provides dividends in terms of our understanding of basic biological mechanisms. In this case, an obscure IGFBP seems to be staking a claim to determining why males have different bone structure than females. Even if this claim is only partially correct, it would still represent a fairly dramatic change in our thinking.
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Footnotes |
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Abbreviations: HCAO, Hepatitis C-associated osteosclerosis; IGFBP, IGF binding protein; PTEN, phosphatase and tensin homolog deleted from chromosome 10.
Received February 6, 2008.
Accepted for publication February 8, 2008.
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