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The Localization of Androgen Receptors in Human Bone

Department of Medicine (E.O.A., A.H., J.E.C.), University of Cambridge School of Clinical Medicine, Cambridge; Medical Research Council Bone Research Laboratory (V.K., J.T.T.), Nuffield Orthopaedic Centre, Oxford, United Kingdom

Address all correspondence and requests for reprints to: Dr. J.E. Compston, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Level 5, Box 157, Hills Road, Cambridge, CB2 2QQ United Kingdom.

	Abstract

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Androgens have important effects on the human skeleton, and deficiency has been associated with bone loss in both males and females. The skeletal actions of androgens may be mediated directly via the androgen receptor (AR) or indirectly via the estrogen receptor after aromatization to estrogens. The presence of androgen receptors has been demonstrated in bone cells and chondrocytes in vitro, but their presence in human bone in situ has not been reported. In order to provide further evidence for a direct action of androgens on bone via androgen receptors, we have used specific monoclonal antibodies to investigate the expression of human AR in normal developing and osteophytic bone of both sexes.

In the growth plates from the developing bone, androgen receptors were predominantly expressed in hypertrophic chondrocytes and in osteoblasts at sites of bone formation. They were also observed in osteocytes in the bone, and in mononuclear cells and endothelial cells of blood vessels within the bone marrow. In the osteophytes, androgen receptors were widely distributed at sites of endochondral ossification in proliferating, mature, and hypertrophic chondrocytes and at sites of bone remodeling in osteoblasts. They were also expressed in osteocytes and mononuclear cells within the bone marrow. The pattern and number of cells expressing the receptor was similar in both sexes.

Our results show for the first time the presence and distribution of androgen receptors in normal developing human and osteophytic bone in situ and further provide evidence for a direct action of androgens on bone and cartilage cells.

	Introduction

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ANDROGENS have important effects on the human skeleton in both males and females. Hypogonadism in men is associated with increased bone turnover and bone loss (1, 2, 3, 4), which is reversed after treatment with androgens (5, 6). Similarly, in hirsute women, androgens maintain normal bone mass in spite of low or undetectable estradiol levels (7), and in postmenopausal women, androgen therapy prevents bone loss (8, 9, 10).

However, the action mechanism of androgens on bone is still a subject of debate. Recent data indicate that the skeletal actions of androgens may be partially mediated via the estrogen receptor after conversion to estrogens by the action of aromatase (11). Osteoporosis has been observed in male and female siblings, caused by a mutation in the aromatase gene (12), and a point mutation in the estrogen receptor gene in a 28-yr-old male was associated with delayed closure of the epiphyses and markedly decreased bone mineral density (13). However, there is evidence that androgens have a direct effect on bone, as suggested by the presence of androgen receptors (AR) in human and rat osteoblast-like cell lines as well as normal human osteoblast-like cells in vitro (11, 14, 15). The nonaromatizable androgen, dihydrotestosterone has been shown to increase alkaline phosphatase (ALP) activity, synthesis of type 1 procollagen, and insulin-like growth factor II (IGF-II) messenger RNA in SAOS2 osteosarcoma cell lines (16). In humans, circulating levels of adrenal androgens, including dehydroepiandrosterone, are strongly associated with bone density in aging women (17). In men, the syndrome of androgen insensitivity caused by mutations in the androgen receptor gene is associated with osteopenia (18).

To further substantiate the evidence for the direct action of androgens on bone tissue, we have used a specific monoclonal antibody to the human AR to investigate the expression of these receptors in human bone in situ, using normal growing human bone and osteophytic bone from adults of both sexes.

	Materials and Methods

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Tissue preparation

Samples of tibial growth plates were obtained from three males (11, 15, and 15 yr) and two females (9 and 12 yr) during surgery for corrective osteotomy, while osteophytes were obtained from patients undergoing surgery for shoulder joint replacement. Informed written consent and ethics committee approval were obtained. Sections of adenocarcinoma of the prostate were used as a positive control and were kindly provided by the Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK.

The human osteophytes were embedded in 5% (w/v) polyvinyl alcohol (Sigma, Poole, Dorset, UK), while the tibial growth plates and prostatic adenocarcinoma tissue were fixed in formalin and embedded in paraffin.

Immunolocalization

Immunolocalization was performed using a specific mouse monoclonal antibody to the human AR (BioGenex, San Ramon, CA). This antibody was developed against specific peptide sequences (301–320) in the N-terminus of the human AR. It has been well-characterized and does not cross-react with estrogen, progesterone, or glucocorticoid receptors (19). The presence of AR has been demonstrated in many human tissues using this antibody (20).

Briefly, the sections of osteophytes were fixed in 4% paraformaldehyde while the sections of tibial growth plates and prostatic adenocarcinoma tissue were dewaxed in inhibisol and rehydrated in alcohol and water. After blocking nonspecific binding sites, with blocking serum [10% normal goat serum; 1% bovine serum albumin (BSA)], the sections were incubated with a final concentration of 2.5 µg/mL of the primary antibody overnight at 4 C. After washing, they were incubated with the second antibody, biotinylated sheep anti-mouse antibody (Sigma) at a final dilution of 1/200 in PBS for 1 h. The sections were further incubated with Avidin Biotin Complex for 30 min (Vector Lab, Peterborough, UK), and the signal was detected using a DAB substrate (Vector Lab). The sections were mounted, and photographs were taken using an Olympus BH-2 microscope (Olympus, Tokyo, Japan).

Cytochemistry

Osteoclasts and osteoblasts in the osteophytes were identified by tartrate-resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) respectively, using serial unfixed and undecalcified sections. For the TRAP reaction, the sections were incubated in 0.1 m citrate buffer pH 4.5 containing 1 mmol/L naphthol AS-BI phosphate (Sigma) and 10 mmol/L sodium tartrate (21). The sections were washed in cold distilled water containing 50 mmol/L sodium fluoride, post-coupled in 0.1 mmol/L acetate buffer pH 6.2 containing 2.2 mmol/L Fast Garnet GBC (Sigma) at 22 C for 30 sec and washed in distilled water before mounting in aqueous mountant.

For the ALP reaction, sections were incubated for 2 min at 22 C in a 2% solution (w/v) of sodium barbitone containing magnesium chloride (0.2 mmol/L, -naphthyl acid phosphate (0.16 mmol/L; Sigma) and Fast Red TR (4.0 mmol/L; Sigma) at a final pH of 9.0 (22). The sections were washed in distilled water, counterstained with 0.01% methyl green, and mounted in aqueous mountant.

Histological staining

Chondrocytes in the sections of growth plates and osteophytes were identified morphologically using 1% toluidine blue (pH 4.5).

Quantitation

The number of cells expressing the AR was assessed by cell counts. The total cell count and the number of stained cells for each designated region was assessed in at least three sections in three to four fields per section at 200 x magnification using an Olympus BH-2 microscope. The approximate number of cells expressing the receptors were recorded as a percentage of the total number of cells of the same phenotype.

	Results

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Morphologically, the sections of human tibial growth plates exhibited areas of endochondral bone formation with undifferentiated, proliferating, mature, and hypertrophic chondrocytes in the cartilage. Numerous osteoblasts, osteoclasts, and osteocytes were also present at sites of bone modeling/remodeling, while mononuclear cells and blood vessels were observed in the bone marrow (Fig. 1, A and B). Similarly, sections of osteophytes also showed areas of endochondral ossification and bone remodeling.

View larger version (141K): [in this window] [in a new window]   Figure 1. The localization of AR in normal tibial growth plate and adult osteophytic human bone. A) Morphologically, sections of the growth plate consist of areas of endochondral ossification with undifferentiated (small arrow head), proliferating (large arrow heads), mature (small arrow) and hypertrophic (large arrow) chondrocytes. Bar = 80 µm. An inset of an area of the primary spongiosa is shown in B. B) Numerous osteoblasts (small arrow heads) and multinucleated osteoclasts (large arrow heads) were observed on the bone surface. Mononuclear cells within the bone marrow were also seen (arrows). Bar = 60 µm. C) In the growth plate, AR was predominantly expressed by hypertrophic chondrocytes (large arrow heads). Minimal expression was observed in the mature chondrocytes (small arrow heads). The receptors were rarely observed in the proliferating chondrocytes (arrow). D) In the primary spongiosa, the AR was predominantly and highly expressed by osteoblasts at modeling sites (arrow heads). Bar = 20 µm. E) In the osteophytes, AR was also observed at sites of endochondral ossification in undifferentiated (small arrow heads), proliferating (large arrow heads), mature (small arrows), and hypertrophic-like (large arrow) chondrocytes. Bar = 80 µm. F) A higher magnification of E) showing proliferating, mature, and hypertrophic-like chondrocytes (large arrows, small arrows, and very large arrows respectively) Bar = 40 µm. G) At sites of bone remodeling, the receptors were highly expressed in the osteoblasts (small arrow heads) and also in mononuclear cells in the bone marrow (large arrow heads). Bar = 40 µm. H) AR was not detected in osteoclasts (small arrow heads) Bar = 40 µm. B, Bone; C, Cartilage; BM, Bone marrow.

View larger version (83K): [in this window] [in a new window]   Figure 2. The localization of AR in osteocytes, mononuclear cells within the bone marrow and in endothelial cells of blood vessels. A) AR was also observed in some osteocytes (small arrow heads) and in osteoblasts (large arrow head) within the primary spongiosa of the tibial growth plates. Bar = 60 µm. B) In the bone marrow of the growth plates, the receptors were detected in mononuclear cells (large arrow heads) and in endothelial cells of blood vessels (small arrow). Red blood cells are also seen (arrow). Bar = 60 µm. C) Blood vessels within the bone with endothelial cells (small arrow heads), and mononuclear cells within the bone marrow (large arrow heads). Arrow indicates red blood cell. Bar = 60 µm. D) Negative control (mouse antiurease at the same concentration as the primary antibody) showing absence of staining in osteoblasts (large arrow heads) and osteocytes (small arrow heads) at a modeling site. Bar = 60 µm. E) Specific staining was also absent in osteoblasts when the primary antibody was omitted from the staining procedure. Bar = 60 µm. F) Absence of staining in the negative control (as in D) was also observed in the mononuclear cells in the bone marrow. Bar = 60 µm. G) High expression of AR was observed in the positive control (adenocarcinoma of the prostate), especially in the less differentiated cells (arrow heads) Bar = 60 µm. B, Bone; BM, Bone marrow.

The pattern and number of cells expressing the receptor was similar in both sexes; although the number of cells expressing AR was not compared statistically because of the relatively small number of samples.

In sections of adenocarcinoma of the prostate (positive control), AR were localized to the nuclei of malignant cells with a higher level of expression in the less differentiated cells (Fig. 2G). In the negative controls, no specific staining was observed using mouse antiurease antibody at the same concentration as the primary antibody (Fig. 2, D and F). There was also absence of staining when the primary antibody was omitted from the staining procedure (Fig. 2E).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Our results show for the first time the presence and distribution of AR in normal developing human and adult osteophytic bone. The receptors were most highly expressed by osteoblasts and hypertrophic chondrocytes. They were also detected in osteocytes and in mononuclear and endothelial cells of blood vessels within the bone marrow.

The high expression of AR in osteoblasts at sites of bone modeling and remodeling suggests that androgens may have important effects on osteoblast function. The actions of androgens may be mediated either directly as testosterone or after reduction to dihydrotestosterone by the action of 5- reductase. The presence of this enzyme has been demonstrated in osteoblast-like cell lines (MG-63 and HOS) (23). Dihydrotestosterone has been shown to stimulate proliferation (24) and differentiation of osteoblasts by increasing insulin-like growth factor II receptors and transforming growth factor ß (25), suggesting a direct action on osteoblast function. However, the possibility that testosterone may also mediate some of its actions directly via AR cannot be ruled out.

In contrast to the work of Mizuno, et al. (26), who showed the presence of AR in mouse osteoclast-like cells in vitro, we did not observe the presence of AR in human osteoclasts. This may be a result of differences between species or may indicate differences in cell responses in vitro and in vivo. However, the presence of AR in mononuclear cells within the bone marrow is consistent with another study (27), which also suggested that androgens regulate osteoclastogenesis and bone mass indirectly via interleukin-6 and that this process was AR-dependent (28). The actions of androgens on osteoclasts may therefore be mediated indirectly via stromal cells or osteoblasts. Other mechanisms by which androgens may inhibit bone resorption include reduction of prostaglandin E2 production (29), inhibition of the effects of parathyroid hormone (PTH) on osteoblasts (30), and inhibition of osteoclastogenesis (27, 31).

In the growth plate and at sites of endochondral ossification in the osteophytes, AR was predominantly expressed by hypertrophic chondrocytes. Specific dihydrotestosterone-binding sites have been demonstrated in cultured human fetal epiphyseal chondrocytes (32), and our results further provide information on the probable sites of action of androgens on the growth plate.

The presence of AR was also observed in newly formed osteocytes and in the endothelial cells of blood vessels within the bone marrow. Apoptosis has been observed in osteocytes following estrogen withdrawal (33). Also parathyroid hormone has been shown to affect signal-transduction of mechanical stress in osteocytes (34). The role of androgens, if any, on osteocyte function is poorly understood and requires further investigation. The presence of AR has been reported in large arteries in humans (35). The detection of these receptors in endothelial cells of blood vessels within the bone would be consistent with a role for androgens in the process of angiogenesis.

The pattern and number of cells expressing AR was similar in both males and females, although we were unable to perform a statistical comparison because of the relatively small number of samples used. Our findings of the expression of AR in human bone is similar to the expression of estrogen receptor messenger RNA in bone as reported by Kusec, et al. (36), where estrogen receptor messenger RNA was observed in chondrocytes and osteoblasts, but not in osteoclasts or mature osteocytes. The presence and distribution of AR in growing normal human and adult osteophytic bone in situ further supports the evidence for a direct action of androgens via AR in bone in both males and females.

Received March 20, 1997.

Accepted July 11, 1997.

	References

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1. Seeman E, Melton III LJ, O’Fallon WM, Riggs BL. 1983 Risk factors for spinal osteoporosis in men. Am J Med. 75:977–938.[CrossRef][Medline]
2. Greenspan SL, Neer RM, Ridgway EL, Klibanski A. 1986 Osteoporosis in men with hyperprolactinaemic hypogonadism. Ann Intern Med. 104:777–782.
3. Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, Cowley WF. 1987 Osteoporosis in men with idiopathic hypogonadism. Ann Intern Med. 106:352–361.
4. Goldray D, Weisman Y, Jaccard N, Merdler C, Chen J, Matzin H. 1993 Decreased bone density in elderly men treated with the gonadotrophin releasing hormone agonist Decapeptyl. J Clin Endocrinol Metab. 76:288–290.[Abstract]
5. Finkelstein JS, Klibanski A, Neer RM, et al. 1989 Increases in bone density during treatment of men with idiopathic hypogonadotrophic hypogonadism. J Clin Endocrinol Metab. 69:776–783.[Abstract]
6. Greenspan SL, Oppenheimer DS, Klibanski A. 1989 Importance of gonadal steroids to bone mass in men with hyperprolactinaemic hypogonadism. Ann Intern Med. 106:354–361.
7. Dixon JE, Rodin A, Murby B, Chapman MG, Fogelman I. 1989 Bone mass in hirsute women with androgen excess. Clin Endocrinol (Oxf). 30:271–277.[Medline]
8. Johansen JS, Hassager C, Podenphant J, et al. 1989 Treament of postmenopausal osteoporosis: is the anabolic nandrolone decanoate a candidate? Bone Miner. 6:77–86.[CrossRef][Medline]
9. Chesnut C, Ivey JL, Gruber HE, et al. 1983 Stanozolol in postmenopausal osteoporosis: therapeutic efficacy and possible mechanisms of action. Metabolism. 32:571–580.[CrossRef][Medline]
10. Need AG, Horowitz M, Walker CJ, Chatterton BE, Chapman K, Nordin BEC. 1989 Cross-over study of fat-corrected forearm mineral content during nandrolone decanoate therapy for osteoporosis. Bone. 10:3–6.[Medline]
11. Vanderschueren D, Bouillon R. 1995 Androgens and bone. Calcif Tissue Int. 56:341–346.[CrossRef][Medline]
12. Morishoma A, Grumbach MM, Simpson ER, Fisher C, Qiu K. 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 80:3689–3698.[Abstract]
13. Smith EP, Boyd J, Frank GR, et al. 1994 Estrogen resistance caused by a mutation in the estrogen receptor gene in man. N Engl J Med. 331:1056–1061.[Abstract/Free Full Text]
14. Colvard DS, Eriksen EF, Keeling PE, et al. 1989 Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci USA. 86:854–857.[Abstract/Free Full Text]
15. Orwoll ES, Stribraska L, Ramsey EE, Keeman EJ. 1991 Androgen receptors in osteoblast-like cell lines. Calcif Tissue Int. 49:183–187.[Medline]
16. Kasperk CH, Faeling K, Borcsok I, Zieggler R. 1996 Effects of androgen on sub-populations of the human osteosarcoma cell-line SAOS2. Calcif Tissue Int. 58:376–382.[Medline]
17. Nordin BEC, Robertson A, Seaman RF, et al. 1985 The relationship between calcium absorption, serum dehydroepiandrosterone and vertebral bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 60:651–657.[Abstract]
18. Soule SG, Conway G, Prelevic GM, Prentice M, Ginsburg J, Jacob HS. 1995 Osteopenia as a feature of the androgen insensitivity syndrome. Clin Endocrinol (Oxf). 43:671–675.[Medline]
19. Zegers ND, Claasen E, Neelen C, et al. 1991 Epitope prediction and conformation for the human androgen receptor: generation of monoclonal antibodies for multiassay performance following the synthetic peptide strategy. Biochim Biophys Acta. 1073:23–32.[Medline]
20. Ruizeveld de Winter A, Trapman J, Vermey M, Mulder E, Zegers ND, Van der Kwast TH. 1991 Androgen receptor expression in human tissues: an immunohistochemical study. J Histochem Cytochem. 39:927–936.[Abstract]
21. Loveridge N, Dean V, Goltzman D, Hendy GN. 1991 Bioactivity of parathyroid hormone and parathyroid hormone-like peptide: agonist and antagonist activities of amino-terminal fragments as assessed by the cytochemical bioassay and in situ biochemistry. Endocrinology. 12:1938–1946.
22. Bradbeer JN, Lindsay PC, Reeve J. 1994 Fluctuation of mineral apposition rate at individual bone remodelling sites in human iliac cancellous bone: independent correlations with osteoid width and osteoblastic alkaline phosphatase. J Bone Miner Res. 9:1679–1686.[Medline]
23. Shimodaaira K, Fujikawqa I, Okura F, Shimuzu Y, Saito H, Yanaihara T. 1996 Osteoblast cells (MG-63 and HOS) have aromatase and 5-alpha reductase activities. Biochem Mol Biol Int. 39:109–116.[Medline]
24. Musuyama A, Ouchi Y, Sato F, Hosoi T, Nakamura T, Orimo H. 1992 Characteristics of steroid hormone receptors in cultured LC3T3–E1 osteoblastic cells and effect of steroid hormones in cell proliferation. Calcif Tissue Int. 51:376–381.[CrossRef][Medline]
25. Benz DJ, Haussler MR, Thomas MA, Speelman B, Komin BS. 1991 High affinity androgen binding and androgenic regulation of 1(1)-pro collagen and transforming growth factor-ß steady state messenger ribonucleic acid levels in human osteoblast-like osteosarcoma cells. Endocrinology. 128:2723–2730.[Abstract]
26. Mizuno Y, Hosoi T, Onuchi Y, Chang C, Orimo H. 1994 Immonocytochemical identification of androgen receptor in mouse osteoclast-like multinucleated cells. Calcif Tissue Int. 54:325–326.[CrossRef][Medline]
27. Bellido T, Girasole G, Jilka RL, Crabb D, Manolagas SC. 1993 Demonstration of androgen receptors in bone marrow stromal cells and their role in the regulation of transcription from the human interleukin-6 gene promoter. J Bone Miner Res. 8(Suppl 1):5131.
28. Bellido T, Jilka RL, Boyce BF, et al. 1995 Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. J Clin Invest. 95:2886–2895.
29. Pilbeam CC, Raisz LG. 1990 Effects of androgens on parathyroid and interleukin-1-stimulated prostaglandin production in cultured neonatal mouse calvariae. J Bone Miner Res. 5:1183–1188.[Medline]
30. Fukayama S, Tashjian AH. 1989 Direct modulation by androgens of the response of human bone cells (SaOS-2) to human parathyroid hormone (PTH) and PTHrp. Endocrinology. 125:1789–1794.[Abstract]
31. Ryaby JT, Magee FP, Khin NA, Fitzsimmons RJ, Baylink DJ. 1993 Down-regulation of osteoclastogenic potential in vivo by combined ac/dc magnetic fields. J Bone Miner Res. 8(Suppl 1):5273.
32. Carrascosa A, Audi L, Ferrandez MA, Ballabriga A. 1990 Biological effects of androgens and identification of specific dihydrotestosterone-binding sites in cultured human fetal epiphyseal chondrocytes. J Clin Endocrinol Metab. 70:134–140.[Abstract]
33. Tomkinson A, Reeve J, Shaw RW, Noble BS. 1996 The death of osteocytes by apoptosis in human bone is observed following estrogen withdrawal by GNRH analogs. J Bone Miner Res. 11(Suppl 1):1.
34. Miyauchi A, Notoya K, Takagi Y, et al. 1996 The role of PTH-activated volume-sensitive calcium influx pathways of osteocytes in the signal transduction of mechanical stress. J Bone Miner Res. 11(Suppl 1):270.
35. Kimura N, Mizokami A, Oonuma T, Sasano H, Nagara H. 1993 Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues. J Histochem Cytochem. 41:671–678.[Abstract]
36. Kusec V, Virdi AS, Prince R, Kenwright J, Triffitt JT. 1996 Localization of estrogen receptor mRNA in skeletal cells by in situ hybridization. In: Papapoules SE, ed. Proceedings of the World Congress on Osteoporosis. Amsterdam: Elsevier BV; p 29–35.

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