This study investigated the effects of Humulus japonicus extract supplementation on bone growth and microstructural properties in male and female rats, with a particular focus on the JAK2/STAT5/IGF-1 signaling pathway. Three-week-old Sprague–Dawley rats were assigned to different groups receiving a normal diet (ND), growth hormone (GH), or varying doses of H. japonicus extract: low (L; 73 mg/kg body weight [bw]/day), medium (M; 146 mg/kg bw/day), and high (H; 292 mg/kg bw/day) for four weeks. The results demonstrated that the H group exhibited significant increases in femur and tibia lengths, trabecular and cortical bone mineral density, and growth plate thickness compared with the ND group. Furthermore, the H group demonstrated elevated serum and hepatic IGF-1 and IGFBP-3 levels, as well as enhanced phosphorylation of JAK2 and STAT5. The findings suggest that H. japonicus supplementation promotes longitudinal bone growth by stimulating growth plate activity and modulating the JAK2/STAT5-IGF-1 signaling pathway. This research indicates that H. japonicus extract could potentially be used as a natural therapeutic agent to support skeletal development and maintain bone health.
Get full access to this article
View all access options for this article.
References
1.
HaraguchiR, KitazawaR, KoharaY, et al.Recent insights into long bone development: Central Role of hedgehog signaling pathway in regulating growth plate. Int J Mol Sci, 2019; 20(23):5840; doi: 10.3390/ijms20235840
2.
ZhouE, LuiJ. Physiological regulation of bone length and skeletal proportion in mammals. Exp Physiol, 2021; 106(2):389–395; doi: 10.1113/EP089086
3.
BeierF, LeaskTA, HaqueS, et al.Cell cycle genes in chondrocyte proliferation and differentiation. Matrix Biol, 1999; 18(2):109–120; doi: 10.1016/s0945-053x(99)00009-8
KobayashiT, LuJ, CobbBS, et al.Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. Proc Natl Acad Sci U S A, 2008; 105(6):1949–1954; doi: 10.1073/pnas.0707900105
6.
KiepeD, CiarmatoriS, HoeflichA, et al.Insulin-like growth factor (IGF)-I stimulates cell proliferation and induces IGF binding protein (IGFBP)-3 and IGFBP-5 gene expression in cultured growth plate chondrocytes via distinct signaling pathways. Endocrinology, 2005; 146(7):3096–3104; doi: 10.1210/en.2005-0324
7.
LongobardiL, O’RearL, AakulaS, et al.Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res, 2006; 21(4):626–636; doi: 10.1359/jbmr.051213
8.
WenC, XuL, XuX, et al.Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment. Arthritis Res Ther, 2021; 23(1):277; doi: 10.1186/s13075-021-02662-0
9.
TahimicCG, WangY, BikleDD. Anabolic effects of IGF-1 signaling on the skeleton. Front Endocrinol (Lausanne), 2013; 4:6; doi: 10.3389/fendo.2013.00006
10.
EkenstedtKJ, SonntagWE, LoeserRF, et al.Effects of chronic growth hormone and insulin-like growth factor 1 deficiency on osteoarthritis severity in rat knee joints. Arthritis Rheum, 2006; 54(12):3850–3858; doi: 10.1002/art.22254
11.
YakarS, RosenCJ, BeamerWG, et al.Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest, 2002; 110(6):771–781; doi: 10.1172/JCI15463
12.
SungB, ChungJW, BaeHR, et al.Humulus japonicus extract exhibits antioxidative and anti-aging effects via modulation of the AMPK-SIRT1 pathway. Exp Ther Med, 2015; 9(5):1819–1826; doi: 10.3892/etm.2015.2302
13.
JungTW, KimHC, ShinYK, et al.Humulus japonicus stimulates thermogenesis and ameliorates oxidative stress in mouse adipocytes. J Mol Endocrinol, 2019; 63(1):1–9; doi: 10.1530/JME-19-0010
14.
WalkerEG, LoKR, PahlMC, et al.An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: A randomized, crossover clinical trial. Am J Clin Nutr, 2022; 115(3):925–940; doi: 10.1093/ajcn/nqab418
15.
KangEJ, KimHJ, ChoiJH, et al.Humulus japonicus extract ameliorates collagen-induced arthritis in mice through regulation of overall articular inflammation. Int J Mol Med, 2020; 45(2):417–428; doi: 10.3892/ijmm.2019.4417
16.
KimOK, YunJM, LeeM, et al.A mixture of Humulus japonicus increases longitudinal bone growth rate in Sprague Dawley rats. Nutrients, 2020; 12(9):2625; doi: 10.3390/nu12092625
17.
HuX, LiJ, FuM, et al.The JAK/STAT signaling pathway: From bench to clinic. Signal Transduct Target Ther, 2021; 6(1):402; doi: 10.1038/s41392-021-00791-1
18.
WójcikM, KrawczyńskaA, AntushevichH, et al.Post-Receptor inhibitors of the GHR-JAK2-STAT pathway in the growth hormone signal transduction. Int J Mol Sci, 2018; 19(7):1843; doi: 10.3390/ijms19071843
19.
WangY, BikleDD, ChangW. Autocrine and paracrine actions of IGF-i signaling in skeletal development. Bone Res, 2013; 1(3):249–259; doi: 10.4248/BR201303003
20.
ChenY, KeJ, LongX, et al.Insulin-like growth factor-1 boosts the developing process of condylar hyperplasia by stimulating chondrocytes proliferation. Osteoarthritis Cartilage, 2012; 20(4):279–287; doi: 10.1016/j.joca.2011.12.013
21.
ZhangM, XuJ, WangT, et al.The dipeptide Pro-Gly promotes IGF-1 expression and secretion in HepG2 and female mice via PepT1-JAK2/STAT5 pathway. Front Endocrinol (Lausanne), 2018; 9:424; doi: 10.3389/fendo.2018.00424
22.
ZhangF, HeQ, TsangWP, et al.Insulin exerts direct, IGF-1 independent actions in growth plate chondrocytes. Bone Res, 2014; 2:14012; doi: 10.1038/boneres.2014.12
23.
ZhangW, ShenX, WanC, et al.Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: Differential signalling via Akt and ERK. Cell Biochem Funct, 2012; 30(4):297–302; doi: 10.1002/cbf.2801
24.
Dalle CarbonareL, GianniniS. Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest, 2004; 27(1):99–105; doi: 10.1007/BF03350919
25.
HansenSG, LichtensteinMB, JohansenKK, et al.Normal bone mineral density and bone microarchitecture in adult males with high and low risk of exercise addiction. Front Sports Act Living, 2022; 4:1021442; doi: 10.3389/fspor.2022.1021442
26.
AğırdilY. The growth plate: A physiologic overview. EFORT Open Rev, 2020; 5(8):498–507; doi: 10.1302/2058-5241.5.190088
HallettSA, MatsushitaY, OnoW, et al.Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment. Elife, 2021; 10:e64513; doi: 10.7554/eLife.64513
