AJP - Endo Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 293: E410-E415, 2007. First published May 1, 2007; doi:10.1152/ajpendo.00042.2007
0193-1849/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/E410    most recent
00042.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takeuchi, S.
Right arrow Articles by Miyakawa, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takeuchi, S.
Right arrow Articles by Miyakawa, S.

Production of sex steroid hormones from DHEA in articular chondrocyte of rats

Satsuki Takeuchi,1 Naoki Mukai,1 Tetsuya Tateishi,2 and Shumpei Miyakawa1

1Doctoral Program of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba; and 2Biomaterials Center, National Institute for Materials Science, Ibaraki, Japan

Submitted 17 January 2007 ; accepted in final form 18 April 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dehydroepiandrosterone (DHEA), a precursor of sex steroid hormones, is synthesized by cholesterol side-chain cleavage cytochrome P-450 and 17{alpha}-hydroxylase cytochrome P-450 mainly from cholesterol and converted to testosterone and estrogen by 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-HSD, and aromatase cytochrome P-450. Although sex steroid hormones have important effects in the protection of articular cartilage, it is unclear whether articular cartilage has a local steroidogenic enzymatic machinery capable of metabolizing DHEA. This study was aimed to clarify whether steroidogenesis-related enzymes are expressed in articular chondrocytes, whether expression levels are changed by DHEA, and whether articular chondrocytes are capable of synthesizing sex steroid hormones from DHEA. Articular chondrocytes isolated from adult rats were cultured with DHEA for 3 days. All of the mRNA expressions of steroidogenesis-related enzymes were detected in cultured articular chondrocytes of rats, but the mRNA expression levels of testosterone and estradiol in cultured media increased after the addition of DHEA. These findings provided the first evidence that articular chondrocytes expressed steroidogenesis-related enzyme genes and that they are capable of locally synthesizing sex steroid hormones locally from DHEA.

testosterone; estrogen; dehydroepiandrosterone; steroidogenesis-related enzymes

OSTEOARTHRITIS (OA) is the most common arthropathy and results in significant disability in the elderly. Pathological characteristics of OA are progressive loss of articular cartilage, subchondral bone remodeling, bone spur formation, and synovial inflammation. In postmenopausal women, a gradual decrease of sex steroid hormones, i.e., estrogen, may result in elevated risk factors for OA (9, 22). It is well known that hormone replacement therapy reduces the prevalence and incidence of OA in postmenopausal women (27, 37, 43). Additionally, long-term estrogen replacement therapy (ERT) significantly reduces the severity of OA lesions in ovariectomized cynomolgus monkeys (12). Recently, several studies reported that dehydroepiandrosterone (DHEA), classified as an adrenal androgen, has a protective role in maintaining articular cartilage (15, 16). Thus levels of sex steroid hormones, such as androgens, estrogen, and DHEA, are linked to degenerative or protective effects on articular cartilage.

Sex steroid hormones are mainly secreted by ovary, testis, and adrenal cortex (34). DHEA and its sulfate-bound form (DHEAS) are important precursors of sex steroid hormones in peripheral tissues. DHEA and DHEAS, mainly secreted by the adrenal gland and ovary, are the most abundant hormones in mammals including humans. For instance, plasma levels of DHEA in humans are 100 to 500 times higher than testosterone and 1,000 to 10,000 times higher than estradiol (18). Several peripheral tissues express DHEA and DHEAS metabolic enzymes and are capable of local formation of sex steroid hormones (19, 33). The biosynthesis of active androgens and estrogens is achieved by the following steroidogenesis-related enzymes: cholesterol side-chain cleavage cytochrome P-450 (P450scc), 17{alpha}-hydroxylase cytochrome P-450 (P450c17), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-HSD, and aromatase cytochrome P-450 (P450arom) (17, 42). DHEA is synthesized from cholesterol and pregnenolone by the metabolic pathways of P450scc and P450c17 (42). Testosterone is synthesized through the metabolism of DHEA by 3beta-HSD and 17beta-HSD, and estrogens are converted from androgens catalyzed by P450arom (17, 18). During a preliminary study, 17beta-HSD activity was detected in articular chondrocytes of rabbits (3). However, the expression of other steroidogenesis-related enzymes and the capability of synthesizing sex steroid hormones in articular cartilage have remained unclear. Elucidating local biosynthesis of active sex steroid hormones in articular chondrocytes would provide a deeper insight into the mechanism by which DHEA confers a protective effect on articular cartilage.

For this reason, we hypothesized that steroidogenesis-related enzymes, including P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom, are present in the articular cartilage and that they locally synthesize sex steroid hormones from circulating DHEA. In the present study, we examined whether steroidogenesis-related enzymes are expressed in articular chondrocytes, whether expression levels of these enzymes are changed by DHEA, and whether articular chondrocytes are capable of synthesizing sex steroid hormones from DHEA in primary cultured chondrocytes of adult rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Isolation of chondrocytes. The experimental protocols were approved by the Committee on Animal Research at the University of Tsukuba. Adult female Sprague-Dawley rats were obtained from Charles River Japan (Yokohama, Japan). The cartilage was collected from the knee and shoulder joints bilaterally under sterile conditions and was washed with calcium- and magnesium-free Dulbecco's phosphate-buffered saline and minced into small pieces. Chondrocytes were released from articular cartilage after being digested by 0.2% collagenase type II (Worthington Biochemical, Lakewood, NJ) in high-glucose Dulbecco's modified Eagle's medium (DMEM; Sigma, St. Louis, MO) containing 1% anti-penicillin-streptomycin solution (Sigma) at 37°C. After the removal of undigested cartilage using a 70-µm nylon sieve, the chondrocytes were collected by centrifugation, washed twice, and resuspended in DMEM supplemented with 10% fetal bovine serum, containing 1% penicillin-streptomycin (culture medium). The cells were seeded in T-25 culture flasks in culture medium under an atmosphere of 5% CO2 and 95% air at 37°C. The culture medium was changed every 48 to 72 h.

Chondrocyte culture and treatment. At confluence, chondrocytes were harvested with 0.25% trypsin-0.02% EDTA (Gibco, Rockville, MD) and seeded in a six-well culture plate at a density of 5 x 104 cells/cm2. When a confluence level of 80% to 90% was reached, the cells were cultured with 0, 100, 200, or 300 µM of DHEA (Sigma). DHEA was dissolved in 95% ethanol. After 3 days, the cultured media samples were harvested and the cells were detached. All experiments were performed only with the first passaged cells.

The ATDC5 chondrocyte cell line was used as a positive control, purchased from RIKEN cell bank (Ibaraki, Japan) and maintained as described by Atsumi et al. (2). ATDC5 was cultured for 7 days, and cells were detached.

Total RNA extractions and reverse transcription. Total RNA was extracted from the cultured chondrocytes using Isogen (Nippon Gene, Toyama, Japan) according to the manufacturer's instructions. The complementary DNA from prepared RNA (2 µg) was synthesized with omniscript reverse transcriptase (Qiagen, Tokyo, Japan) using an oligo (dT) primer at 37°C for 60 min.

Semiquantitative and real-time quantitative PCR. The mRNA expression level of type II collagen was analyzed by semiquantitative PCR. Each PCR reaction contained 10 mM Tris·HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, dNTP at 2 mM each type II collagen or glyceraldehyde-3-phosphate dehydrogenase (GAPDH) primers at 0.5 µM each, and 0.5 U/µl rTaq DNA polymerase (Toyobo, Osaka, Japan). The sequence of the oligonucleotide was as follows: type II collagen forward: 5'-TGGTGCATCTGGAGACAGAG-3', type II collagen reverse: 5'-GCCAGAAGTACCCTGATCTC-3', GAPDH forward: 5'-CCCCTTCATTGACCTCAACTAC-3', and GAPDH reverse: 5'-ACAACCTGGTCCTCAGTGTAGC-3'.

PCR was performed using a PCR thermal cycler (iCycler Version 3.021; Bio-Rad, Hercules, CA). The cycle profile included denaturation for 1 min at 94°C, annealing for 1 min at 58°C, and extension for 1 min at 72°C. The amplified PCR products were electrophoresed on 1.5% agarose gels, stained with ethidium bromide, visualized by an ultraviolet transilluminator, and photographed (Toyobo).

The mRNA expression levels of P450scc (28), P450c17 (10), 3beta-HSD (45), 17beta-HSD (11), P450arom (13), and GAPDH (39) were analyzed by real-time quantitative PCR with TaqMan (FAM) probe using an ABI Prism 7500 Sequence Detector (Perkin-Elmer Applied Biosystems, Foster, CA). Each PCR amplification used the following profile: 1 cycle of 95°C for 10 min, 40 cycles of 95°C for 15 s, and 1 cycle of 60°C for 1 min. The expression of GAPDH mRNA was used as an internal control. The quantitative values of P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom mRNA were normalized by that of GAPDH mRNA expression. The sequences of the oligonucleotide are shown in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1. Real-time RT-PCR primer sequences

 
Concentrations of testosterone and estradiol. Concentrations of testosterone and estradiol in cultured media were determined using a commercial enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA) kits. The level of testosterone was determined using a testosterone EIA kit (Cayman Chemical, Ann Arbor, MI) and the level of estradiol using a 17beta-estoradiol ELISA kit (Japan EnviroChemicals, Tokyo, Japan). All techniques and materials used in this analysis were in accordance with the manufacturer's protocol. All samples were assayed in duplicate.

Statistical analysis. All experiments were performed in triplicate. Results were expressed as means ± SE of three experiments. Statistical comparisons were carried out by Kruskal-Wallis test to examine differences between individual date points. Statistical significance was set at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Messenger RNA expression of type II collagen, a marker of articular chondrocytes, was detected in cultured cells of rats (Fig. 1). Additionally, to investigate the effect of adding DHEA to cultured articular chondrocytes, the levels of mRNA expression of type II collagen were measured after adding DHEA and changing the culture media; however, no changes were observed in them. The levels of GAPDH mRNA expression, an internal control, also did not change (data not shown).


Figure 1
View larger version (73K):
[in this window]
[in a new window]

  		Fig. 1. Messenger RNA expression of type II collagen in cultured articular chondrocytes of rats (A and B) compared with positive control, namely, ATDC5.

 
To investigate whether articular chondrocytes possess steroidogenic capabilities, we examined the existence of P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom mRNA and the response to mRNA expression of steroidogenesis-related enzymes after adding DHEA to articular chondrocytes (Figs. 2 and 3). Consistent with our hypothesis, mRNA expression of P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom was detected in articular chondrocytes of rats. However, levels of mRNA expression of P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom in articular chondrocytes did not change after the addition of DHEA.


Figure 2
View larger version (18K):
[in this window]
[in a new window]

  		Fig. 2. Expression of mRNA of steroidogenesis-related enzymes involving side-chain cleavage cytochrome P-450 (P450scc; A) and 17{alpha}-hydroxylase cytochrome P-450 (P450c17; B) after addition of dehydroepiandrosterone (DHEA; 0, 100, 200, and 300 µM) to articular chondrocytes in cultured media. Data are expressed as means ± SE. AU, arbitrary units.

 

Figure 3
View larger version (16K):
[in this window]
[in a new window]

  		Fig. 3. Expression of mRNA of steroidogenesis-related enzymes involving 3beta-hydroxysteroid dehydrogenase (3beta-HSD; A), 17beta-HSD (B), and aromatase cytochrome P-450 (P450arom; C) after addition of DHEA (0, 100, 200, and 300 µM) to articular chondrocytes in cultured media. Data are expressed as means ± SE.

 
By adding increasing concentrations of DHEA to articular chondrocytes, we sought to investigate whether articular chondrocytes are capable of using DHEA as a substrate or metabolite precursor for local steroidogenesis (Fig. 4). Our results confirmed that the concentrations of testosterone and estradiol in cultured media increased after the addition of DHEA at 100 to 300 µM.


Figure 4
View larger version (21K):
[in this window]
[in a new window]

  		Fig. 4. Concentration of testosterone (A) and estradiol (B) after addition of DHEA (0, 100, 200, and 300 µM) to articular chondrocytes in cultured media. Data are expressed as means ± SE. *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study revealed the expression of mRNA of steroidogenesis-related enzymes, including P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom, in articular chondrocytes of rats. Importantly, concentrations of testosterone and estradiol in cultured media increased by the addition of DHEA. These findings are novel and important in that articular cartilage is capable of locally synthesizing sex steroid hormones from DHEA.

Numerous studies have previously demonstrated the expression of steroidogenesis-related enzymes in various tissues, for instance, in testis, ovary, adrenal gland, brain, bone, and skeletal muscle (1, 29, 31, 32, 41). Any peripheral tissue can participate in the uptake of numerous circulating DHEAS, and DHEA can be converted to testosterone and estrogen through 3beta-HSD, 17beta-HSD, and P450arom (35, 38). The present study showed mRNA expression of all steroidogenesis-related enzymes, including P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom, detected in articular chondrocytes of rats. A preliminary study showed that only 17beta-HSD is present in the cultured chondrocytes of rabbits (4). Thus the present results suggest that articular cartilage is one of the tissues to possess a steroidogenesis system. Additionally, in the present study, the levels of mRNA expression of P450scc, P450c17, 3beta-HSD, 17beta-HSD, and P450arom in articular chondrocytes did not change when DHEA was added. These results indicate that DHEA may induce an enhancement in the transcriptional regulation of steroidogenesis-related enzymes in articular chondrocytes.

The functional significance of gonadal-derived sex steroid hormones is well known. Recently, it has been proposed that other tissue-derived sex steroid hormones in nervous, adipose, and adrenal tissues, among others, play an important role in the physiology and pathophysiology of cells in these tissues (5). Interestingly, we demonstrated an increase in production of testosterone and estradiol from DHEA in cultured media of articular chondrocytes. Evidence supporting a role for local sex steroid hormones in articular chondrocytes has been widely reported (9, 12, 27, 37, 43); however, the exact source of these hormones is unclear. Our results clearly demonstrate the presence and activity of local metabolic machinery or a pathway for the substrate DHEA and the subsequent secretion of testosterone and estrogens in cultured media of articular cartilage. In fact, this study detected the genetic expression of 3beta-HSD, 17beta-HSD, and P450arom, which are metabolic enzymes of DHEA, in the articular chondrocytes. Thus the articular chondrocytes of rats may metabolize DHEA through the metabolic pathway of these enzymes and synthesize testosterone and estradiol into the cell. Therefore, we propose the existence of a local secreting system of testosterone and estrogens using DHEA.

Aging-induced impairment in sex steroid hormones, particularly in postmenopausal women, increases the risk of OA. Therefore, understanding the role of sex steroid hormones in the protection of articular chondrocytes is critical for developing an effective therapeutic strategy for OA. Other studies have reported that women who received ERT for at least 5 yr showed an increase in the volume of knee cartilage compared with those who did not receive ERT (43). Similarly, the use of hormone replacement therapy in women protected recipients from developing OA of the hip and knee (27, 37). In addition, estrogen improved OA-induced molecular responses in human chondrocytes (20). On the other hand, the decreasing testosterone levels were significantly associated with an increasing OA score in women with OA of the hand (36). One study of healthy men reported a positive correlation between tibial cartilage volume and serum testosterone levels (6). The present study revealed a local production of sex steroid hormones from DHEA in chondrocytes. DHEA and DHEAS can be found in synovial fluid (7). Because articular cartilage is an avascular tissue (23), DHEA may be taken up from synovial fluid and metabolized by articular chondrocytes. Furthermore, to confirm this, in vivo studies are necessary to ascertain the concentration of DHEA in synovial fluid. Although no receptor for DHEA has been identified until now (42), the expression of receptors for androgen and estrogen (estrogen receptor {alpha} and beta) has been detected in articular chondrocytes (26, 40). In recent studies, both in vitro and in vivo, DHEA was shown to improve the imbalance of transcriptional regulation between matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 in articular cartilage, resulting in protection against articular cartilage loss (15, 16, 44). Thus our results support the idea that the local formation of sex steroid hormones from DHEA in chondrocytes may participate in a molecular mechanism underlying sex steroid-induced improvement of OA. Additionally, our study detected DHEA-metabolic enzymes (e.g., 3beta-HSD, 17beta-HSD, and P450arom) in the articular chondrocytes. Plasma levels of DHEA and DHEAS levels in human adults are markedly higher than corresponding levels of testosterone and estradiol (18). Therefore, DHEA and DHEAS are potential components in therapeutic strategies for OA.

The intravital normal condition of cultured cells may alter with any change in external microenvironments, including change of culture media, addition of DHEA, and incubating oxygen saturation. In the present study, the type II collagen and GAPDH mRNA expression levels did not change after an addition of DHEA and a change of culture media in the cultured articular chondrocytes. Thus the cell culture-induced external microenvironment may not affect the cell condition in the present study. However, we cannot rule out the possibility of the involvement of external microenvironments in the present results. Therefore, future studies should clarify this issue and examine in vivo in the current experimental setting. The sequences of PCR primers that we used in the present study were designed from the following sequences: P450scc (28), 3beta-HSD (45), 17beta-HSD (11), and P450arom (13) refer to ovary; and P450c17 (10) refers to testis. Additionally, 3beta-HSD in rat exists as four different isoforms (types I-IV) (30). In the present study, we used PCR primers of 3beta-HSD, which detects the common sequences of both type I and type II expressed in ovary, testis, brain, etc. 17beta-HSD in rat exists as 10 different isoforms (types I-VIII, X, and XII) (14, 21, 24), and we used PCR primer of 17beta-HSD type I, expressed in ovary, testis, bone, etc. P450scc, P450c17, and P450arom genes did not exist in any isoforms. Accordingly, the sequence of detected steroidogenesis-related enzyme genes in articular chondrocytes may correspond to those in ovary or testis; however, we did not carry out cloning and sequencing of steroidogenesis-related enzyme genes in articular chondrocytes. Future studies should examine the precise sequences of these genes in the articular chondrocytes in the current experimental setting. The fact that the cells used in this study confirmed detection by mRNA expression of type II collagen, which accounts for 90–95% of the collagen in articular cartilage (8), proved that these are articular chondrocytes. We therefore inferred that steroidogenesis-related enzymes exist in the nuclear region of articular chondrocytes because we used these cells. However, we did not examine the cultured cells immunohistochemically. These enzymes are expressed in cytoplasmic region of ovary and testis; therefore, we considered that protein expressions of these enzymes exist in the cytoplasmic region of articular chondrocytes. Future studies should clarify this issue and examine the localization of these enzymes not only in vitro but also in vivo in the current experimental setting.

In conclusion, our findings indicate the presence of steroidogenesis-related enzymes in articular chondrocytes of adult rats and show that sex steroid hormones are locally synthesized from DHEA in articular chondrocytes. Therefore, the chondroprotective effects of sex steroid hormones may occur intracrinology in the articular chondrocytes of rats.


   ACKNOWLEDGMENTS
 
We thank Katsuji Aizawa and Motoyuki Iemitsu for great support in experiment and manuscript writing.


   FOOTNOTES
 

Address for reprint requests and other correspondence: N. Mukai, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8574, Japan (e-mail: mukai{at}taiiku.tsukuba.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Aizawa K, Iemitsu M, Maeda S, Jesmin S, Otsuki T, Mowa CN, Miyauchi T, Mesaki N. Expression of steroidogenic enzymes and synthesis of sex steroid hormones from DHEA in skeletal muscle of rats. Am J Physiol Endocrinol Metab 292: E577–E584, 2007.[Abstract/Free Full Text]
  2. Atsumi T, Miwa Y, Kimata K, Ikawa Y. A chondrogenic cell line derived from a differentiating culture of AT805 teratocarcinoma cells. Cell Differ Dev 30: 109–116, 1990.[CrossRef][Web of Science][Medline]
  3. Baulieu EE. Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab 81: 3147–3151, 1996.[CrossRef][Web of Science][Medline]
  4. Bellino FL. Estrogen metabolism, not biosynthesis, in rabbit articular cartilage and isolated chondrocytes: a preliminary study. Steroids 57: 507–510, 1992.[CrossRef][Web of Science][Medline]
  5. Carreau S, Genissel C, Bilinska B, Lavallet J. Sources of oestrogen in the testis and reproductive tract of the male. Int J Androl 22: 211–23, 1999.[CrossRef][Web of Science][Medline]
  6. Cicuttini FM, Wluka A, Bailey M, O'Sullivan R, Poon C, Yeung S, Ebeling PR. Factors affecting knee cartilage volume in healthy men. Rheumatology (Oxford) 42: 258–262, 2003.[CrossRef][Medline]
  7. Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Anddrogens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann NY Acad Sci 966: 131–142, 2002.[Web of Science][Medline]
  8. Eyre DR, Wu JJ, Apone S. A growing family of collagens in articular cartilage: identification of 5 genetically distinct types. J Rheumatol 14 Spec No: 25–27, 1987.
  9. Felson DT, Nevitt CM. The effects of estrogen on osteoarthritis. Curr Opin Rheumatol 10: 269–272, 1998.[CrossRef][Medline]
  10. Fevold HR, Lorence MC, McCarthy JL, Trant JM, Kagimoto M, Waterman MR, Mason JI. Rat P450 (17 alpha) from testis: characterization of a full-length cDNA encoding a unique steroid hydroxylase capable of catalyzing both delta4- and delta 5-steroid-17, 20-lyase reactions. Mol Endocrinol 3: 968–975, 1989.[Abstract/Free Full Text]
  11. Ghersevich S, Nokelainen P, Poutanen M, Orava M, Autio-Harmainen H, Rajaniemi H, Vihko R. Rat 17beta-hydroxysteroid dehydrogenase type 1: primary structure and regulation of enzyme expression in rat ovary by diethylstilbestrol and gonadotropins in vivo. Endocrinology 135: 1477–1487, 1994.[Abstract]
  12. Ham KD, Loeser RF, Lindgren BR, Carlson CS. Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. Arthritis Rheum 46: 1956–1964, 2002.[CrossRef][Web of Science][Medline]
  13. Hickey GJ, Krasnow JS, Beattie WG, Richards JS. Aromatase cytochrome P450 in rat ovarian granulose cells before and after luteinization: adenosine 3', 5'-monophosphate-dependent and independent regulation. Cloning and sequencing of rat aromatase cDNA and 5' genomic DHA. Mol Endocrinol 4: 3–12, 1990.[Abstract/Free Full Text]
  14. Ivell R, Balvers M, Anand RJ, Paust HJ, Mckinnell C, Sharpe R. Differentiation-dependent expression of 17beta-hydroxysteroid dehydrogenase, type10, in the rodent testis: effect of aging in leydig cells. Endocrinology 144: 3130–3137, 2003.[Abstract/Free Full Text]
  15. Jo H, Ahn HJ, Kim EM, Kim HJ, Seong SC, Lee IB, Lee MC. Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis. Arthritis Rheum 50: 2531–2538, 2004.[CrossRef][Web of Science][Medline]
  16. Jo H, Park JS, Kim EM, Jung MY, Lee SH, Seong SC, Park SC, Kim HJ, Lee MC. The invitro effects of dehydroepiandrosterone on human osteoarthritic chondrocytes. Osteoarthritis Cartilage 11: 585–594, 2003.[CrossRef][Web of Science][Medline]
  17. Labrie F. Adrenal androgens and intracrinology. Semin Reprod Med 22: 299–309, 2004.[CrossRef][Web of Science][Medline]
  18. Labrie F, Luu-The V, Belanger A, Lin SX, Simard J, Pelletier G, Labrie C. Is dehydroepiandrosterone a hormone? J Endocrinol 187: 169–196, 2005.[Abstract/Free Full Text]
  19. Labrie F, Luu-The V, Lin SX, Simard J, Labrie C, El-Alfy M, Pelletier G, Belanger A. Intracrinology: role of the family of 17beta-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol 25: 1–16, 2000.[Abstract]
  20. Lee YJ, Lee EB, Kwon YE, Lee JJ, Cho WS, Kim HA, Song YW. Effect of estrogen on the expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and tissue inhibitor of metalloproteinase-1 in osteoarthritis chondrocytes. Rheumatol Int 23: 282–288, 2003.[CrossRef][Web of Science][Medline]
  21. Luu-The V. Analysis and characteristics of multiple types of human 17beta-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol 76: 143–151, 2001.[CrossRef][Web of Science][Medline]
  22. Malemud CJ. Fundamental pathways in osteoarthritis: an overview. Front Biosci 4: 659–661, 1999.[CrossRef]
  23. Mankin HJ. The response of articular cartilage to mechanical injury. J Bone Joint Surg Am 64: 460–466, 1982.[Free Full Text]
  24. Mindnich R, Moller G, Adamski J. The role of 17 beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 218: 7–20, 2004.[CrossRef][Web of Science][Medline]
  25. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 49: 421–432, 1998.[CrossRef][Medline]
  26. Nasatzkv E, Schwartz Z, Soskolne WA, Brooks BP, Dean DD, Bovan BD, Ornov A. Evidence for receptors specific for 17 beta-estradiol and testosterone in chondrocyte cultures. Connect Tissue Res 30: 277–294, 1994.[Web of Science][Medline]
  27. Nevitt MC, Cummings SR, Lane NE, Hochberg MC, Scott JC, Pressman AR, Genant HK, Cauley JA. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 156: 2073–2080, 1996.[Abstract/Free Full Text]
  28. Oonk RB, Krasnow JS, Beattie WG, Richards JS. Cyclic AMP-dependent and -independent regulation of cholesterol side chain cleavage cytochrome P-450 (P-450scc) in rat ovarian granulose cells and corpora lutea. cDNA and deduced amino acid sequence of rat P-450scc. J Biol Chem 25: 21934–21942, 1989.
  29. Oz OK, Millsaps R, Welch R, Birch J, Zerwekh JE. Expression of aromatase in the human growth plate. J Mol Endocrinol 27: 249–253, 2001.[Abstract]
  30. Payne AH, Abbaszade IG, Clarke TR, Bain PA, Park CH. The multiple murine 3 beta-hydroxysteroid dehydrogenase isoforms: structures, function, and tissue- and developmentally specific expression. Steroids 62: 169–175, 1997.[CrossRef][Web of Science][Medline]
  31. Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev 25: 947–970, 2004.[Abstract/Free Full Text]
  32. Sasano H, Uzuki M, Sawai T, Nagura H, Matsunaga G, Kashimoto O, Harada N. Aromatase in human bone tissue. J Bone Miner Res 12: 1416–1423, 1997.[CrossRef][Web of Science][Medline]
  33. Simpson E, Rubin G, Clyne C, Robertson K, O'Donnell L, Jones M, Davis S. The role of local estrogen biosynthesis in males and females. Trends Endocrinol Metab 11: 184–188, 2000.[CrossRef][Web of Science][Medline]
  34. Simpson ER. Aromatization of androgens in women: current concepts and findings. Fertil Steril 77: 6–10, 2002.
  35. Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol 86: 225–230, 2003.[CrossRef][Web of Science][Medline]
  36. Sowers MF, Hochberg M, Crabbe JP, Muhich A, Crutchfield M, Updike S. Association of bone mineral density and sex hormone levels with osteoarthritis of the hand and knee in premenopausal women. Am J Epidemiol 143: 38–47, 1996.[Abstract/Free Full Text]
  37. Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study. Ann Rheum Dis 56: 432–434, 1997.[Abstract/Free Full Text]
  38. Tiidus PM. Can estrogens diminish exercise induced muscle? Can J Appl Physiol 20: 26–38, 1995.[Web of Science][Medline]
  39. Tso JY, Sun XH, Kao TH, Reece KS, Wu R. Isolation and characterization of rat and human glyceraldehydes-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res 13: 2485–2502, 1985.[Abstract/Free Full Text]
  40. Ushiyama T, Ueyama H, Inoue K, Ohkubo I, Hukuda S. Expression of genes for estrogen receptors alpha and beta in human articular chondrocytes. Osteoarthritis Cartilage 7: 560–566, 1999.[CrossRef][Web of Science][Medline]
  41. Van Der Eerden BC, Van De Ven J, Lowik CW, Wit JM, Karperien M. Sex steroid metabolism in the tibial growth plate. Endocrinology 143: 4048–4055, 2002.[Abstract/Free Full Text]
  42. Walter LM. Androgen biosynthesis from cholesterol to DHEA. Mol Endocrinol 198: 7–14, 2000.
  43. Wluka AE, Davis SR, Bailey M, Stuckey SL, Cicuttini FM. Users of oestrogen replacement therapy have more knee cartilage than non-users. Ann Rheum Dis 60: 332–336, 2001.[Abstract/Free Full Text]
  44. Wu LD, Yu HC, Xiong Y, Feng J. Effect of dehydroepiandrosterone on cartilage and synovium of knee joints with osteoarthritis in rabbits. Rheumatol Int 27: 79–85, 2006.[CrossRef][Web of Science][Medline]
  45. Zhao HF, Labrie C, Simard J, de Launoit Y, Trudel C, Martel C, Rheaume E, Dupont E, Luu-The V, Pelletier G, Labrie F. Characterization of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase cDNAs and differential tissue-specific expression of the corresponding mRNAs in steroidogenic and peripheral tissues. J Biol Chem 266: 583–593, 1991.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
J. L. Vingren, W. J. Kraemer, D. L. Hatfield, J. M. Anderson, J. S. Volek, N. A. Ratamess, G. A. Thomas, J.-Y. Ho, M. S. Fragala, and C. M. Maresh
Effect of resistance exercise on muscle steroidogenesis
J Appl Physiol, December 1, 2008; 105(6): 1754 - 1760.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
L. Maneix, G. Beauchef, A. Servent, Y. Wegrowski, F. X. Maquart, N. Boujrad, G. Flouriot, J. P. Pujol, K. Boumediene, P. Galera, et al.
17{beta}-Oestradiol up-regulates the expression of a functional UDP-glucose dehydrogenase in articular chondrocytes: comparison with effects of cytokines and growth factors
Rheumatology, March 1, 2008; 47(3): 281 - 288.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/E410    most recent
00042.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takeuchi, S.
Right arrow Articles by Miyakawa, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takeuchi, S.
Right arrow Articles by Miyakawa, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.