Decorin, a growth hormone-regulated protein in humans

in European Journal of Endocrinology
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  • 1 Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • 2 School of Medicine, Western Sydney University, Blacktown Clinical School and Research Centre, Blacktown Hospital, Blacktown, New South Wales, Australia
  • 3 School of Computing, Engineering and Mathematics, Western Sydney University, Penrith, New South Wales, Australia
  • 4 Centres of Health Research, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  • 5 School of Medicine, University of New South Wales, New South Wales, Australia

Correspondence should be addressed to V Birzniece; Email: v.birzniece@westernsydney.edu.au

Context

Growth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein, stimulates connective tissue accretion and muscle hypertrophy. Whether GH and testosterone regulate decorin in humans is not known.

Objective

To determine whether decorin is stimulated by GH and testosterone.

Design

Randomized, placebo-controlled, double-blind study.

Participants and Intervention

96 recreationally trained athletes (63 men, 33 women) received 8 weeks of treatment followed by a 6-week washout period. Men received placebo, GH (2 mg/day), testosterone (250 mg/week) or combination. Women received either placebo or GH (2 mg/day).

Main outcome measure

Serum decorin concentration.

Results

GH treatment significantly increased mean serum decorin concentration by 12.7 ± 4.2%; P < 0.01. There was a gender difference in the decorin response to GH, with greater increase in men than in women (∆ 16.5 ± 5.3%; P < 0.05 compared to ∆ 9.4 ± 6.5%; P = 0.16). Testosterone did not significantly change serum decorin. Combined GH and testosterone treatment increased mean decorin concentration by 19.5 ± 3.7% (P < 0.05), a change not significantly different from GH alone.

Conclusion

GH significantly increases circulating decorin, an effect greater in men than in women. Decorin is not affected by testosterone. We conclude that GH positively regulates decorin in humans in a gender-dimorphic manner.

Abstract

Context

Growth hormone (GH) stimulates connective tissue and muscle growth, an effect that is potentiated by testosterone. Decorin, a myokine and a connective tissue protein, stimulates connective tissue accretion and muscle hypertrophy. Whether GH and testosterone regulate decorin in humans is not known.

Objective

To determine whether decorin is stimulated by GH and testosterone.

Design

Randomized, placebo-controlled, double-blind study.

Participants and Intervention

96 recreationally trained athletes (63 men, 33 women) received 8 weeks of treatment followed by a 6-week washout period. Men received placebo, GH (2 mg/day), testosterone (250 mg/week) or combination. Women received either placebo or GH (2 mg/day).

Main outcome measure

Serum decorin concentration.

Results

GH treatment significantly increased mean serum decorin concentration by 12.7 ± 4.2%; P < 0.01. There was a gender difference in the decorin response to GH, with greater increase in men than in women (∆ 16.5 ± 5.3%; P < 0.05 compared to ∆ 9.4 ± 6.5%; P = 0.16). Testosterone did not significantly change serum decorin. Combined GH and testosterone treatment increased mean decorin concentration by 19.5 ± 3.7% (P < 0.05), a change not significantly different from GH alone.

Conclusion

GH significantly increases circulating decorin, an effect greater in men than in women. Decorin is not affected by testosterone. We conclude that GH positively regulates decorin in humans in a gender-dimorphic manner.

Introduction

Growth hormone (GH) and testosterone are potent anabolic hormones that interact positively in regulating the muscle structure and function (1, 2, 3, 4). The effects of GH on collagen synthesis, fat mass, lean tissue and physical function are amplified by testosterone. Similarly the effects of testosterone in hypopituitary and normal men are greater when co-administered with GH (4, 5, 6, 7, 8, 9). Both GH and testosterone increase collagen markers, with GH imparting a greater effect, whereas testosterone amplifies the effect of GH on collagen markers, such as PIIINP (4, 5).

Decorin, a small leucine-rich proteoglycan, is a myokine and connective tissue protein (10, 11). Decorin is produced in response to exercise, and it stimulates skeletal muscle differentiation and repair (12, 13, 14, 15, 16). Decorin induces myogenic satellite cell proliferation by inhibiting responsiveness to TGF-β1 (17). In vitro overexpression of decorin enhances the proliferation and differentiation of skeletal muscle cells by repressing the activity of myostatin, an inhibitor of muscle cell growth and differentiation (18). Furthermore, decorin overexpression in muscle increases the expression of promyogenic genes, while repressing genes involved in muscle atrophy (16). Decorin also stimulates connective tissue collagen synthesis and regulates connective tissue formation in skeletal muscle (19, 20, 21).

No studies to date have assessed the effects of GH or testosterone on decorin production in humans. The aim of the present study is to investigate whether GH and testosterone regulate circulating decorin in healthy men and women.

Subjects and methods

Healthy recreational athletes aged 18–40 years, who had regularly participated in at least twice weekly exercise sessions in the past year were recruited, as previously described (5). Exclusion criteria were participation in sports competitions at the state or national level, self-reported abuse of performance-enhancing drugs, history of diabetes mellitus, cardiovascular, hepatic or renal disease, known cancer or positive urine screen for prohibited anabolic agents. 96 athletes (63 men and 33 women) were included in the study. Participants were instructed not to change their diet or exercise level throughout the study. All study participants provided written informed consent. The study was approved by St. Vincent’s Hospital Human Research Ethics Committee, NSW Australia and registered with the Australian New Zealand Clinical Trials Registry ACTRN012605000508673.

This was a double-blind placebo-controlled randomized study, as previously described (5). Briefly, women were assigned to receive either 2 mg/day GH (n = 17) or placebo (n = 16). Men were assigned to receive 2 mg/day GH (n = 15), 250 mg/week testosterone (n = 16), GH plus testosterone (n = 16), or double placebo (n = 16). Participants self-administered GH (Somatropin, 1 mg/mL; Novo Nordisk) or matched placebo subcutaneously each evening at dosages of 1.0 mg/day in the first week, 1.5 mg/day in the second week and 2.0 mg/day for the remaining 6 weeks. Testosterone (Sustanon, Organon, Oss, the Netherlands; 250 mg/week) or placebo was administered from the end of the third week as weekly intramuscular injections (5). The effects of the interventions on IGF-I, collagen peptides, body composition and physical function have been published (4, 5).

We examined whether serum decorin concentrations were affected by supplementation with GH in men and women, and testosterone in men. We also investigated whether co-administration with testosterone enhanced the effects of GH alone. We compared changes in decorin to GH-regulated proteins, IGF-I and collagen peptides and changes in body composition. Body composition was measured by dual-energy x-ray absorptiometry and included lean body mass (LBM) assessment and a functional measure of muscle mass – body cell mass (derived by subtracting extracellular water from the LBM), as previously described (4).

Assays

Serum samples were collected at baseline (week 0), during treatment (week 4), end of treatment (week 8) and after a 6-week washout period (week 14) and stored at −80°C for analysis. Decorin levels were measured using the Decorin Human ELISA kit (Abcam) according to manufacturer instructions. Serum samples were diluted 100-fold and all samples for each subject were measured in duplicates in the same assay run. The sensitivity of the assay is <1.5 pg/mL with >93% recovery rate. The intra-assay and inter-assay coefficients of variation (CVs) were <2% and <12%, respectively. IGF-1, testosterone, PINP, PIIINP and ICTP were assayed as previously described (5).

Statistical analysis

Treatment effects on decorin levels were evaluated by one-way ANOVA for repeated measures, followed by Dunnett’s post hoc multiple comparison test to evaluate treatment effects at individual time points. Data are expressed as mean ± s.e.m. Multiplicity adjusted P values are reported, and differences relative to the placebo group considered significant at P < 0.05. Spearman’s rank correlation was used for the analysis of correlation between the serum decorin concentration and the IGF axis, collagen markers and body composition. Unadjusted P values are reported, and correlations were considered significant at P < 0.05. Statistical analyses were performed using RStudio (Boston, MA, USA) (22).

Results

Table 1 shows the baseline characteristics of the 96 subjects, serum concentration of decorin, and previously reported measures of body mass index (BMI), IGF-1 and PIIINP (5). There were no significant differences in the baseline decorin levels between the treatment groups. At baseline, there was a positive and significant correlation between serum levels of decorin and the collagen marker, PIIINP (R = 0.34, P < 0.01). There were no significant associations between baseline serum decorin concentrations and any other endpoint measures.

Table 1

Baseline characteristics of the study subjects. The table shows the age, body mass index (BMI), and serum levels of IGF-1, testosterone, PIIINP and decorin of the subjects in various treatment groups. Data are shown as mean ± s.e.m.

TreatmentAge (year)BMI (kg/m2)IGF-1 (µg/L)T (nmol/L)PIIINP (µg/L)Decorin (pg/mL)
Women
 Placebo27.8 ± 1.322.8 ± 0.8137 ± 10.01.4 ± 0.24.5 ± 0.36481 ± 203
 GH29.7 ± 1.622.9 ± 0.7124 ± 7.91.2 ± 0.23.7 ± 0.26127 ± 349
Men
 Placebo28.9 ± 1.326.1 ± 0.8110 ± 9.621.9 ± 1.93.4 ± 0.25748 ± 275
GH25.2 ± 1.423.8 ± 0.7128 ± 9.725.3 ± 2.14.2 ± 0.45748 ± 269
T29.0 ± 1.525.4 ± 1.0128 ± 9.523.5 ± 2.04.1 ± 0.36304 ± 448
GH + T26.8 ± 1.324.4 ± 0.7113 ± 10.323.1 ± 1.34.0 ± 0.25953 ± 312

GH, growth hormone; T, testosterone.

Indicative of the effect of intervention, in women GH administration increased IGF-1 by 86 ± 12% (P < 0.0001). In men, IGF-1 significantly (P < 0.0001) increased by 144 ± 23% and 160 ± 24% when treated with GH alone or when combined with testosterone, respectively. Serum testosterone increased significantly (P < 0.01) in men treated with testosterone alone (23.5 ± 2.0 vs 32.2 ± 2.5 nmol/L) or when combined with GH (23.1 ± 1.3 vs 31.2 ± 1.7 nmol/L).

Table 2 shows serum decorin levels during the hormone treatments and withdrawal. The mean decorin concentration increased significantly (P < 0.01) during eight weeks of GH treatment, returning to baseline after withdrawal (Fig. 1A). The increase in decorin concentration was greater in men (16.5 ± 5.3%; P < 0.05, Fig. 1C) than in women (9.4 ± 6.5%; P = 0.16; Fig. 1B). Decorin levels did not change during placebo treatment. Testosterone treatment did not significantly affect circulating decorin levels (∆ 4.2 ± 3.6%; P = 0.30; Fig. 2). Co-administration of testosterone with GH significantly increased decorin levels (∆ 19.5 ± 3.7% P < 0.01; Fig. 2). However, no additive effect of the co-treatment was observed compared to GH alone.

Figure 1
Figure 1

Change in serum decorin concentration in men and women in response to hormone treatment. Data are presented as mean percentage changes in serum decorin at week 4 (during treatment), week 8 (end of treatment) and week 14 (after a 6-week washout period) from baseline (week 0) for: (A) GH treatment group (men and women combined), (B) women and (C) men. Data are mean ± s.e.m. *P < 0.05, **P < 0.01.

Citation: European Journal of Endocrinology 178, 2; 10.1530/EJE-17-0844

Figure 2
Figure 2

Change in serum decorin concentration in men in response to hormone treatment. Mean percentage changes in serum decorin at week 4 (during treatment), week 8 (end of treatment) and week 14 (after a 6-week washout period) from baseline (week 0). Data are shown as mean ± s.e.m. *P < 0.05.

Citation: European Journal of Endocrinology 178, 2; 10.1530/EJE-17-0844

Table 2

Mean serum decorin concentrations before treatment (week 0), during treatment (week 4), end of treatment (week 8) and after a 6-week washout period (week 14). Men received either placebo, GH (2 mg/day), testosterone (250 mg/week), or combined treatments. Women received either placebo or GH (2 mg/day). Data are shown as mean ± s.e.m.

nTreatmentSerum decorin (pg/mL)
Week 0Week 4Week 8Week 14
Women and men32Placebo6114 ± 1816075 ± 2166017 ± 1855838 ± 225
32GH5950 ± 2236452 ± 269a6652 ± 312a5931 ± 252b
Women16Placebo6481 ± 2036220 ± 3296218 ± 2206189 ± 300
17GH6127 ± 3496491 ± 3646591 ± 4345902 ± 352b
Men16Placebo5748 ± 2755930 ± 2855816 ± 2975487 ± 320
15GH5748 ± 2696408 ± 4136721 ± 465a5965 ± 373b
16T6304 ± 4486664 ± 5056547 ± 4925937 ± 426b
16GH + T5953 ± 3126600 ± 355a7061 ± 368a5438 ± 250b

aDecorin significantly different from week 0 within group (P < 0.05); bDecorin at week 14 significantly different from week 8 within group (P < 0.05).

GH, growth hormone; T, testosterone.

Changes in serum decorin correlated significantly (P < 0.001) with changes in IGF-1, PINP, ICTP and PIIINP (Fig. 3). Changes in serum decorin showed significant positive correlation with changes in LBM (R = 0.50; P < 0.001) and body cell mass (R = 0.31; P < 0.05).

Figure 3
Figure 3

Relation between changes in serum decorin concentrations at week 8 from baseline, vs the changes in IGF-1, PINP, ICTP, and PIIINP in men (solid circles) and women (clear circles). The Spearman correlation coefficients and P values are indicated for each correlation.

Citation: European Journal of Endocrinology 178, 2; 10.1530/EJE-17-0844

Discussion

This study investigated whether decorin is regulated by GH or testosterone in humans. Our data demonstrate that GH significantly increases serum decorin concentration with the effect greater in men than in women. Testosterone did not affect decorin and co-treatment did not have additional effect to that of GH alone. The changes in decorin induced by GH correlated with those of other GH-responsive proteins in blood.

Very little is known about decorin regulation by GH or testosterone. To our knowledge, only one previous study undertaken in rodents observed an increase in decorin production in the extracellular matrix of developing incisors in response to GH (23). In young males, GH administration for 2 weeks did not affect decorin mRNA expression in tendon during immobilization; however, circulating decorin was not measured (24). Thus, our study is the first to report that GH stimulates decorin production in humans.

Decorin is a structural protein in the skeletal muscle extracellular matrix and regulates genes for muscle growth and repair (16, 18), suggesting a role in the regulation of muscle structure and function. There is strong evidence that exercise positively regulates decorin gene expression and protein production in muscle, contributing to a rise in blood decorin during exercise (15, 16). Because exercise also stimulates the release of GH (25, 26), our findings provide evidence that the stimulation of decorin production may in part be GH mediated.

As decorin stimulates collagen fibrillogenesis (11), we postulate that the upregulation of decorin by GH may play a role in collagen tissue anabolism. GH stimulates muscle and tendon collagen synthesis (24, 27), and we have previously reported that GH significantly increases the markers PINP and PIIINP, indicative of collagen synthesis (5). Thus, GH exerts a significant positive effect on collagen tissue formation. Decorin is known to play a role in collagen formation and has been shown to bind to collagen types I and III (28, 29). In our study, decorin levels correlated with those of PIIINP, which has particular importance in bone and tendon tissue repair (30). Furthermore, decorin modulates bone collagen matrix assembly and mineralization (31). Thus, decorin plays a role in the structural properties of muscle and bone by positively regulating collagen synthesis, an effect which is co-regulated by GH.

We observed a greater increase in decorin levels in men than in women, in the face of a lower body weight-adjusted dose of GH in men than in women. The actions of GH on a range of biological effects are sexually dimorphic (32, 33, 34, 35). In GH-deficient adults, men are more sensitive to GH replacement therapy than women and exhibit significantly greater responses to GH with regard to IGF-1, body composition and bone metabolism markers (36, 37, 38, 39). This clinically significant gender difference may be attributed to the inhibitory effects of estrogens on the GH receptor signaling in women (40). In this study, GH therapy increased collagen markers (PINP, ICTP, PIIINP) to a much greater extent in men than in women (5). As decorin also is a connective tissue protein, the greater increase in decorin in men could relate to the well-known gender difference in the response to GH.

The gender difference in decorin cannot be explained by testosterone because we did not observe an effect of testosterone either alone or co-administered with GH. Testosterone is a potent stimulator of skeletal muscle anabolism, dose dependently increasing muscle mass (1, 2, 3). Although testosterone substantially amplifies the GH effect on collagen marker PIIINP (5), we observed no significant effect on decorin by the co-administration of these hormones. This implies minimal physiological effect of testosterone on circulating decorin in men.

GH may exert its anabolic effects directly through its receptor or indirectly via actions mediated by IGF-1. Besides increasing the levels of circulating IGF-1, GH stimulates the local production of IGF-1 in tissues such as muscle, tendon and cartilage (41, 42). Our study design does not allow to differentiate GH and IGF-1 effect on decorin. In vitro reports suggest that IGF-1 stimulates decorin production in a dose-dependent manner (43, 44, 45). Furthermore, connective tissue growth factor (CTGF) is an inducer of decorin synthesis (46) and has been shown to bind to IGF-1 to enhance its effects on collagen (47). In Laron syndrome of GH insensitivity, IGF-1 administration increases circulating collagen markers, providing evidence that IGF-1 plays an important role in connective tissue metabolism (48). As decorin levels change in parallel to other connective tissue markers, it is plausible that IGF-1 directly stimulates decorin production. Thus, GH through IGF-1 may regulate circulating decorin.

IGF-1 and PIIINP are endorsed biomarkers for GH doping. In our study, the peak response to GH administration in men was around 140% and 250% increase for IGF-1 and PIIINP, respectively (5). Decorin levels increased by 16.5% during GH administration at supraphysiological doses. After 6 weeks of withdrawal from GH, collagen markers (PINP, ICTP and PIIINP) were significantly higher in the GH group compared to placebo (5), whereas decorin returned to baseline upon GH withdrawal. Furthermore, the rather small increase and large variation in decorin during GH administration in women also indicates that decorin may not have a potential to be used as a marker for GH doping in sport.

There are some limitations to our study. Serum levels of decorin may not reflect tissue concentration of decorin. Furthermore, the effect of testosterone may be apparent if different doses or duration of testosterone administration had been used or patients with hypogonadism are studied instead of healthy adults. Nevertheless, we observed no significant effect on circulating decorin using supraphysiological doses of intramuscular testosterone administration 3–4 times that of normal production rate, indicating that in healthy adults testosterone supplementation does not increase circulating decorin.

In summary, we show that administration of GH in healthy adults increases circulating decorin, with the effect greater in men than in women. Testosterone has no significant effect on decorin concentration. We conclude that GH increases serum decorin levels in a gender-dependent manner. We postulate that the upregulation of decorin by GH may play a role in collagen tissue anabolism, enhancing the structural properties of muscle, tendon and bone.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

World Anti-Doping Agency and the Australian Government.

Acknowledgements

The authors thank all volunteers for their participation in the study; research nurses for clinical assistance; Udo Meinhardt, Anne Nelson, David Clifford, Kin-Chuen Leung, Irene Walker and Kenneth Graham for their input in the original study. Funding was provided by the World Anti-Doping Agency and the Australian Government (through the Anti-Doping Research Program of the Department of Communications, Information Technology and the Arts).

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    Miedel EL, Brisson BK, Hamilton T, Gleason H, Swain GP, Lopas L, Dopkin D, Perosky JE, Kozloff KM & Hankenson KD et al. Type III collagen modulates fracture callus bone formation and early remodeling. Journal of Orthopaedic Research 2015 33 675684. (https://doi.org/10.1002/jor.22838)

    • Search Google Scholar
    • Export Citation
  • 31

    Mochida Y, Parisuthiman D, Pornprasertsuk-Damrongsri S, Atsawasuwan P, Sricholpech M, Boskey AL & Yamauchi M. Decorin modulates collagen matrix assembly and mineralization. Matrix Biology 2009 28 4452. (https://doi.org/10.1016/j.matbio.2008.11.003)

    • Search Google Scholar
    • Export Citation
  • 32

    Dall R, Longobardi S, Ehrnborg C, Keay N, Rosen T, Jorgensen JO, Cuneo RC, Boroujerdi MA, Cittadini A & Napoli R et al. The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group. Journal of Clinical Endocrinology and Metabolism 2000 85 41934200.

    • Search Google Scholar
    • Export Citation
  • 33

    Longobardi S, Keay N, Ehrnborg C, Cittadini A, Rosen T, Dall R, Boroujerdi MA, Bassett EE, Healy ML & Pentecost C et al. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group. Journal of Clinical Endocrinology and Metabolism 2000 85 15051512.

    • Search Google Scholar
    • Export Citation
  • 34

    Gotherstrom G, Bengtsson BA, Bosaeus I, Johannsson G & Svensson J. A 10-year, prospective study of the metabolic effects of growth hormone replacement in adults. Journal of Clinical Endocrinology and Metabolism 2007 92 14421445. (https://doi.org/10.1210/jc.2006-1487)

    • Search Google Scholar
    • Export Citation
  • 35

    Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C & Tobin JD et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002 288 22822292. (https://doi.org/10.1001/jama.288.18.2282)

    • Search Google Scholar
    • Export Citation
  • 36

    Johansson AG. Gender difference in growth hormone response in adults. Journal of Endocrinological Investigation 1999 22 5860.

  • 37

    Burman P, Johansson AG, Siegbahn A, Vessby B & Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. Journal of Clinical Endocrinology and Metabolism 1997 82 550555.

    • Search Google Scholar
    • Export Citation
  • 38

    Hayes FJ, Fiad TM & McKenna TJ. Gender difference in the response of growth hormone (GH)-deficient adults to GH therapy. Metabolism 1999 48 308313. (https://doi.org/10.1016/S0026-0495(99)90077-X)

    • Search Google Scholar
    • Export Citation
  • 39

    Johannsson G, Bjarnason R, Bramnert M, Carlsson LM, Degerblad M, Manhem P, Rosen T, Thoren M & Bengtsson BA. The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. Journal of Clinical Endocrinology and Metabolism 1996 81 15751581.

    • Search Google Scholar
    • Export Citation
  • 40

    Leung KC, Johannsson G, Leong GM & Ho KK. Estrogen regulation of growth hormone action. Endocrine Reviews 2004 25 693721. (https://doi.org/10.1210/er.2003-0035)

    • Search Google Scholar
    • Export Citation
  • 41

    Isgaard J, Nilsson A, Vikman K & Isaksson OG. Growth hormone regulates the level of insulin-like growth factor-I mRNA in rat skeletal muscle. Journal of Endocrinology 1989 120 107112. (https://doi.org/10.1677/joe.0.1200107)

    • Search Google Scholar
    • Export Citation
  • 42

    Sadowski CL, Wheeler TT, Wang LH & Sadowski HB GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. Endocrinology 2001 142 38903900. (https://doi.org/10.1210/endo.142.9.8365)

    • Search Google Scholar
    • Export Citation
  • 43

    D’Avis PY, Frazier CR, Shapiro JR & Fedarko NS. Age-related changes in effects of insulin-like growth factor I on human osteoblast-like cells. Biochemical Journal 1997 324 753760.

    • Search Google Scholar
    • Export Citation
  • 44

    Mullen LM, Best SM, Ghose S, Wardale J, Rushton N & Cameron RE. Bioactive IGF-1 release from collagen-GAG scaffold to enhance cartilage repair in vitro. Journal of Materials Science: Materials in Medicine 2015 26 5325.

    • Search Google Scholar
    • Export Citation
  • 45

    Holladay C, Abbah SA, O’Dowd C, Pandit A & Zeugolis DI. Preferential tendon stem cell response to growth factor supplementation. Journal of Tissue Engineering and Regenerative Medicine 2016 10 783798. (https://doi.org/10.1002/term.1852)

    • Search Google Scholar
    • Export Citation
  • 46

    Vial C, Gutierrez J, Santander C, Cabrera D & Brandan E. Decorin interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity. Journal of Biological Chemistry 2011 286 2424224252. (https://doi.org/10.1074/jbc.M110.189365)

    • Search Google Scholar
    • Export Citation
  • 47

    Lam S, van der Geest RN, Verhagen NA, van Nieuwenhoven FA, Blom IE, Aten J, Goldschmeding R, Daha MR & van Kooten C. Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 2003 52 29752983. (https://doi.org/10.2337/diabetes.52.12.2975)

    • Search Google Scholar
    • Export Citation
  • 48

    Klinger B, Jensen LT, Silbergeld A & Laron Z. Insulin-like growth factor-I raises serum procollagen levels in children and adults with Laron syndrome. Clinical Endocrinology 1996 45 423429. (https://doi.org/10.1046/j.1365-2265.1996.7990809.x)

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

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  • View in gallery

    Change in serum decorin concentration in men and women in response to hormone treatment. Data are presented as mean percentage changes in serum decorin at week 4 (during treatment), week 8 (end of treatment) and week 14 (after a 6-week washout period) from baseline (week 0) for: (A) GH treatment group (men and women combined), (B) women and (C) men. Data are mean ± s.e.m. *P < 0.05, **P < 0.01.

  • View in gallery

    Change in serum decorin concentration in men in response to hormone treatment. Mean percentage changes in serum decorin at week 4 (during treatment), week 8 (end of treatment) and week 14 (after a 6-week washout period) from baseline (week 0). Data are shown as mean ± s.e.m. *P < 0.05.

  • View in gallery

    Relation between changes in serum decorin concentrations at week 8 from baseline, vs the changes in IGF-1, PINP, ICTP, and PIIINP in men (solid circles) and women (clear circles). The Spearman correlation coefficients and P values are indicated for each correlation.

  • 1

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    Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L & Dzekov C et al. Testosterone dose-response relationships in healthy young men. American Journal of Physiology: Endocrinology and Metabolism 2001 281 E1172E1181.

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    Meinhardt U, Nelson AE, Hansen JL, Birzniece V, Clifford D, Leung KC, Graham K & Ho KK. The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial. Annals of Internal Medicine 2010 152 568577. (https://doi.org/10.7326/0003-4819-152-9-201005040-00007)

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    Nelson AE, Meinhardt U, Hansen JL, Walker IH, Stone G, Howe CJ, Leung KC, Seibel MJ, Baxter RC & Handelsman DJ et al. Pharmacodynamics of growth hormone abuse biomarkers and the influence of gender and testosterone: a randomized double-blind placebo-controlled study in young recreational athletes. Journal of Clinical Endocrinology and Metabolism 2008 93 22132222. (https://doi.org/10.1210/jc.2008-0402)

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    Birzniece V, Meinhardt UJ, Umpleby MA, Handelsman DJ & Ho KK. Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver. Journal of Clinical Endocrinology and Metabolism 2011 96 10601067. (https://doi.org/10.1210/jc.2010-2521)

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    Li Y, Li J, Zhu J, Sun B, Branca M, Tang Y, Foster W, Xiao X & Huard J. Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Molecular Therapy 2007 15 16161622. (https://doi.org/10.1038/sj.mt.6300250)

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    Heinemeier KM, Bjerrum SS, Schjerling P & Kjaer M. Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise. Scandinavian Journal of Medicine and Science in Sports 2013 23 e150e161. (https://doi.org/10.1111/j.1600-0838.2011.01414.x)

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    Li X, McFarland DC & Velleman SG. Extracellular matrix proteoglycan decorin-mediated myogenic satellite cell responsiveness to transforming growth factor-beta1 during cell proliferation and differentiation Decorin and transforming growth factor-beta1 in satellite cells. Domestic Animal Endocrinology 2008 35 263273. (https://doi.org/10.1016/j.domaniend.2008.06.002)

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    Kishioka Y, Thomas M, Wakamatsu J, Hattori A, Sharma M, Kambadur R & Nishimura T. Decorin enhances the proliferation and differentiation of myogenic cells through suppressing myostatin activity. Journal of Cellular Physiology 2008 215 856867. (https://doi.org/10.1002/jcp.21371)

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    Doessing S, Heinemeier KM, Holm L, Mackey AL, Schjerling P, Rennie M, Smith K, Reitelseder S, Kappelgaard AM & Rasmussen MH et al. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis. Journal of Physiology 2010 588 341351. (https://doi.org/10.1113/jphysiol.2009.179325)

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  • 30

    Miedel EL, Brisson BK, Hamilton T, Gleason H, Swain GP, Lopas L, Dopkin D, Perosky JE, Kozloff KM & Hankenson KD et al. Type III collagen modulates fracture callus bone formation and early remodeling. Journal of Orthopaedic Research 2015 33 675684. (https://doi.org/10.1002/jor.22838)

    • Search Google Scholar
    • Export Citation
  • 31

    Mochida Y, Parisuthiman D, Pornprasertsuk-Damrongsri S, Atsawasuwan P, Sricholpech M, Boskey AL & Yamauchi M. Decorin modulates collagen matrix assembly and mineralization. Matrix Biology 2009 28 4452. (https://doi.org/10.1016/j.matbio.2008.11.003)

    • Search Google Scholar
    • Export Citation
  • 32

    Dall R, Longobardi S, Ehrnborg C, Keay N, Rosen T, Jorgensen JO, Cuneo RC, Boroujerdi MA, Cittadini A & Napoli R et al. The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group. Journal of Clinical Endocrinology and Metabolism 2000 85 41934200.

    • Search Google Scholar
    • Export Citation
  • 33

    Longobardi S, Keay N, Ehrnborg C, Cittadini A, Rosen T, Dall R, Boroujerdi MA, Bassett EE, Healy ML & Pentecost C et al. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group. Journal of Clinical Endocrinology and Metabolism 2000 85 15051512.

    • Search Google Scholar
    • Export Citation
  • 34

    Gotherstrom G, Bengtsson BA, Bosaeus I, Johannsson G & Svensson J. A 10-year, prospective study of the metabolic effects of growth hormone replacement in adults. Journal of Clinical Endocrinology and Metabolism 2007 92 14421445. (https://doi.org/10.1210/jc.2006-1487)

    • Search Google Scholar
    • Export Citation
  • 35

    Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C & Tobin JD et al. Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 2002 288 22822292. (https://doi.org/10.1001/jama.288.18.2282)

    • Search Google Scholar
    • Export Citation
  • 36

    Johansson AG. Gender difference in growth hormone response in adults. Journal of Endocrinological Investigation 1999 22 5860.

  • 37

    Burman P, Johansson AG, Siegbahn A, Vessby B & Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. Journal of Clinical Endocrinology and Metabolism 1997 82 550555.

    • Search Google Scholar
    • Export Citation
  • 38

    Hayes FJ, Fiad TM & McKenna TJ. Gender difference in the response of growth hormone (GH)-deficient adults to GH therapy. Metabolism 1999 48 308313. (https://doi.org/10.1016/S0026-0495(99)90077-X)

    • Search Google Scholar
    • Export Citation
  • 39

    Johannsson G, Bjarnason R, Bramnert M, Carlsson LM, Degerblad M, Manhem P, Rosen T, Thoren M & Bengtsson BA. The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender. Journal of Clinical Endocrinology and Metabolism 1996 81 15751581.

    • Search Google Scholar
    • Export Citation
  • 40

    Leung KC, Johannsson G, Leong GM & Ho KK. Estrogen regulation of growth hormone action. Endocrine Reviews 2004 25 693721. (https://doi.org/10.1210/er.2003-0035)

    • Search Google Scholar
    • Export Citation
  • 41

    Isgaard J, Nilsson A, Vikman K & Isaksson OG. Growth hormone regulates the level of insulin-like growth factor-I mRNA in rat skeletal muscle. Journal of Endocrinology 1989 120 107112. (https://doi.org/10.1677/joe.0.1200107)

    • Search Google Scholar
    • Export Citation
  • 42

    Sadowski CL, Wheeler TT, Wang LH & Sadowski HB GH regulation of IGF-I and suppressor of cytokine signaling gene expression in C2C12 skeletal muscle cells. Endocrinology 2001 142 38903900. (https://doi.org/10.1210/endo.142.9.8365)

    • Search Google Scholar
    • Export Citation
  • 43

    D’Avis PY, Frazier CR, Shapiro JR & Fedarko NS. Age-related changes in effects of insulin-like growth factor I on human osteoblast-like cells. Biochemical Journal 1997 324 753760.

    • Search Google Scholar
    • Export Citation
  • 44

    Mullen LM, Best SM, Ghose S, Wardale J, Rushton N & Cameron RE. Bioactive IGF-1 release from collagen-GAG scaffold to enhance cartilage repair in vitro. Journal of Materials Science: Materials in Medicine 2015 26 5325.

    • Search Google Scholar
    • Export Citation
  • 45

    Holladay C, Abbah SA, O’Dowd C, Pandit A & Zeugolis DI. Preferential tendon stem cell response to growth factor supplementation. Journal of Tissue Engineering and Regenerative Medicine 2016 10 783798. (https://doi.org/10.1002/term.1852)

    • Search Google Scholar
    • Export Citation
  • 46

    Vial C, Gutierrez J, Santander C, Cabrera D & Brandan E. Decorin interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity. Journal of Biological Chemistry 2011 286 2424224252. (https://doi.org/10.1074/jbc.M110.189365)

    • Search Google Scholar
    • Export Citation
  • 47

    Lam S, van der Geest RN, Verhagen NA, van Nieuwenhoven FA, Blom IE, Aten J, Goldschmeding R, Daha MR & van Kooten C. Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 2003 52 29752983. (https://doi.org/10.2337/diabetes.52.12.2975)

    • Search Google Scholar
    • Export Citation
  • 48

    Klinger B, Jensen LT, Silbergeld A & Laron Z. Insulin-like growth factor-I raises serum procollagen levels in children and adults with Laron syndrome. Clinical Endocrinology 1996 45 423429. (https://doi.org/10.1046/j.1365-2265.1996.7990809.x)

    • Search Google Scholar
    • Export Citation