YK11 promotes osteogenic differentiation of BMSCs and repair of bone defects

in Journal of Molecular Endocrinology
Authors:
Renyi Wang State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Renyi Wang in
Current site
Google Scholar
PubMed Close
,
Yunyu Zhong State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Yunyu Zhong in
Current site
Google Scholar
PubMed Close
,
Qianxin Du State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Qianxin Du in
Current site
Google Scholar
PubMed Close
,
Chengzhi Zhao State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Chengzhi Zhao in
Current site
Google Scholar
PubMed Close
,
Yuhao Wang State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Yuhao Wang in
Current site
Google Scholar
PubMed Close
, and
Jian Pan State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China

Search for other papers by Jian Pan in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0003-1346-048X

Correspondence should be addressed to J Pan: jianpancn@scu.edu.cn

(R Wang and Y Zhong contributed equally to this work)

DOI:
https://doi.org/10.1530/JME-24-0073
Volume/Issue:
Volume 74: Issue 2
Article Type:
Research Article
Article ID:
e240073
Online Publication Date:
07 Jan 2025
Copyright:
© the author(s) 2025
Restricted access
Rent on DeepDyve

Sign up for journal news

The selective androgen receptor (AR) modulator YK11 promotes the anabolism of muscle cells and osteoblastic precursor cells. However, its effects on bone marrow-derived mesenchymal stem cells (BMSCs) and the repair of cranial bone defects are unknown. Here, the effects of different concentrations of YK11 on the osteogenic differentiation of BMSCs were determined. Subsequently, the AR was inhibited to investigate whether the effect of YK11 on the osteogenic differentiation of BMSCs was affected. A model of cranial defects was constructed to investigate the effects of the YK11-equipped hydrogel on cranial defect repair as well as the effects of YK11 on cranial defect repair after inhibiting the AR. Finally, the possible pathway of YK11 regulating the osteogenic differentiation of BMSCs was explored. Our results show 2 μM YK11 promoted the proliferation of BMSCs. A dose of 0.25–4 μM YK11 could promote osteogenesis of BMSCs, and the promoting effect was gradually enhanced with increasing concentration. In vivo, 0.5 and 1 mg/mL YK11 could promote the repair of cranial bone defects. After inhibiting the AR, the effects of YK11 on promoting both the osteogenic differentiation of BMSCs and repair of cranial defects were suppressed. YK11 may regulate the osteogenic differentiation of BMSCs through the BMP2 (bone morphogenetic protein 2)/Smad signaling pathway. In conclusion, YK11 promoted the osteogenic differentiation of BMSCs by activation on the AR. Meanwhile, YK11 promoted the repair of cranial bone defects in rats in vivo. The BMP2/Smad signaling pathway may be involved in the regulation of the osteogenic differentiation of BMSCs by YK11.

Supplementary Materials

Journal of Molecular Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 29 29 24
PDF Downloads 15 15 11

 

  • Collapse
  • Expand
Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© the author(s) 2025
Article ID:
e240073
Article Type:
Research Article
Received Date:
31 Jul 2024
Rev-recd:
13 Nov 2024
Accepted Date:
11 Dec 2024
Print Publication Date:
01 Feb 2025
Online Publication Date:
07 Jan 2025
Keywords:
selective androgen receptor modulator; YK11; BMSCs; osteogenic differentiation; bone defects

  • Almeida M, Laurent MR, Dubois V, et al. 2017 Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97 135–187. (https://doi.org/10.1152/physrev.00033.2015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aro HT, Kulkova J, Moritz N, et al. 2015 Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model. Acta Orthop 86 751–759. (https://doi.org/10.3109/17453674.2015.1074840)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aru B, Akdeniz T, Dağdeviren H, et al. 2023 Testosterone propionate promotes proliferation and viability of bone marrow mesenchymal stem cells while preserving their characteristics and inducing their anti-cancer efficacy. Balkan Med J 40 117–123. (https://doi.org/10.4274/balkanmedj.galenos.2022.2022-10-21)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bennett NC, Gardiner RA, Hooper JD, et al. 2010 Molecular cell biology of androgen receptor signalling. Int J Biochem Cell Biol 42 813–827. (https://doi.org/10.1016/j.biocel.2009.11.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Benvenuti S, Cellai I, Luciani P, et al. 2012 Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells. J Endocrinol Invest 35 365–371. (https://doi.org/10.3275/7739)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bezstarosti H, Metsemakers WJ, van Lieshout EMM, et al. 2020 Management of critical-sized bone defects in the treatment of fracture-related infection: a systematic review and pooled analysis. Arch Orthop Trauma Surg 141 1215–1230. (https://doi.org/10.1007/s00402-020-03525-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boulestreau J, Maumus M, Jorgensen C, et al. 2021 Extracellular vesicles from mesenchymal stromal cells: therapeutic perspectives for targeting senescence in osteoarthritis. Adv Drug Deliv Rev 175 113836. (https://doi.org/10.1016/j.addr.2021.113836)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burg KJ, Porter S & Kellam JF 2000 Biomaterial developments for bone tissue engineering. Biomaterials 21 2347–2359. (https://doi.org/10.1016/s0142-9612(00)00102-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ceruti JM, Oppenheimer FM, Leirós GJ, et al. 2021 Androgens downregulate BMP2 impairing the inductive role of dermal papilla cells on hair follicle stem cells differentiation. Mol Cell Endocrinol 520 111096. (https://doi.org/10.1016/j.mce.2020.111096)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen JF, Lin PW, Tsai YR, et al. 2019 Androgens and androgen receptor actions on bone health and disease: from androgen deficiency to androgen therapy. Cells 8 1318. (https://doi.org/10.3390/cells8111318)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cheng BH, Chu TM, Chang C, et al. 2013 Testosterone delivered with a scaffold is as effective as bone morphologic protein-2 in promoting the repair of critical-size segmental defect of femoral bone in mice. PLoS One 8 e70234. (https://doi.org/10.1371/journal.pone.0070234)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Christiansen AR, Lipshultz LI, Hotaling JM, et al. 2020 Selective androgen receptor modulators: the future of androgen therapy? Transl Androl Urol 9 S135–S148. (https://doi.org/10.21037/tau.2019.11.02)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Corona G, Vena W, Pizzocaro A, et al. 2022 Testosterone supplementation and bone parameters: a systematic review and meta-analysis study. J Endocrinol Invest 45 911–926. (https://doi.org/10.1007/s40618-021-01702-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davis ID, Martin AJ, Stockler MR, et al. 2019 Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381 121–131. (https://doi.org/10.1056/nejmoa1903835)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • de Melo Pereira D & Habibovic P 2018 Biomineralization‐inspired material design for bone regeneration. Adv Healthc Mater 7 e1800700. (https://doi.org/10.1002/adhm.201800700)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dominici M, Le Blanc K, Mueller I, et al. 2006 Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8 315–317. (https://doi.org/10.1080/14653240600855905)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Han H, Wang Y, Curto J, et al. 2022 Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis. Cell Rep 39 110595. (https://doi.org/10.1016/j.celrep.2022.110595)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Heng BC, Bai Y, Li X, et al. 2022 Electroactive biomaterials for facilitating bone defect repair under pathological conditions. Adv Sci 10 e2204502. (https://doi.org/10.1002/advs.202204502)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hwang YJ, Hwang HJ, Go H, et al. 2023 Sword bean (Canavalia gladiata) pods induce differentiation in MC3T3-E1 osteoblast cells by activating the BMP2/SMAD/RUNX2 pathway. Nutrients 15 4372. (https://doi.org/10.3390/nu15204372)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kanno Y, Ota R, Someya K, et al. 2013 Selective androgen receptor modulator, YK11, regulates myogenic differentiation of C2C12 myoblasts by follistatin expression. Biol Pharm Bull 36 1460–1465. (https://doi.org/10.1248/bpb.b13-00231)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kanno Y, Saito N, Saito R, et al. 2022 Differential DNA-binding and cofactor recruitment are possible determinants of the synthetic steroid YK11-dependent gene expression by androgen receptor in breast cancer MDA-MB 453 cells. Exp Cell Res 419 113333. (https://doi.org/10.1016/j.yexcr.2022.113333)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kimura K, Terasaka T, Iwata N, et al. 2017 Combined effects of androgen and growth hormone on osteoblast marker expression in mouse C2C12 and MC3T3-E1 cells induced by bone morphogenetic protein. J Clin Med 6 6. (https://doi.org/10.3390/jcm6010006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Komrakova M, Büchler G, Böker KO, et al. 2022 A combined treatment with selective androgen and estrogen receptor modulators prevents bone loss in orchiectomized rats. J Endocrinol Invest 45 2299–2311. (https://doi.org/10.1007/s40618-022-01865-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kurian AG, Singh RK, Patel KD, et al. 2022 Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics. Bioact Mater 8 267–295. (https://doi.org/10.1016/j.bioactmat.2021.06.027)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lan KC, Wei KT, Lin PW, et al. 2022 Targeted activation of androgen receptor signaling in the periosteum improves bone fracture repair. Cell Death Dis 13 123. (https://doi.org/10.1038/s41419-022-04595-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Landwehr VC, Fretwurst T, Heinen J, et al. 2022 Association of sex steroid hormones and new bone formation rate after iliac onlay grafting: a prospective clinical pilot study. Int J Implant Dent 8 53. (https://doi.org/10.1186/s40729-022-00447-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee SJ, Gharbi A, Shin JE, et al. 2021 Myostatin inhibitor YK11 as a preventative health supplement for bacterial sepsis. Biochem Biophys Res Commun 543 1–7. (https://doi.org/10.1016/j.bbrc.2021.01.030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Luan H, Xu P, Meng Y, et al. 2020 A critical update on the strategies towards modulators targeting androgen receptors. Bioorg Med Chem 28 115554. (https://doi.org/10.1016/j.bmc.2020.115554)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McGovern JA, Griffin M & Hutmacher DW 2018 Animal models for bone tissue engineering and modelling disease. Dis Model Mech 11 dmm033084. (https://doi.org/10.1242/dmm.033084)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mohammadi-Shemirani P, Chong M, Pigeyre M, et al. 2020 Effects of lifelong testosterone exposure on health and disease using Mendelian randomization. Elife 9 e58914. (https://doi.org/10.7554/elife.58914)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morrison SJ & Scadden DT 2014 The bone marrow niche for haematopoietic stem cells. Nature 505 327–334. (https://doi.org/10.1038/nature12984)

  • Qiu WX, Ma XL, Lin X, et al. 2020 Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway. J Cell Mol Med 24 317–327. (https://doi.org/10.1111/jcmm.14729)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ray R, Novotny NM, Crisostomo PR, et al. 2008 Sex steroids and stem cell function. Mol Med 14 493–501. (https://doi.org/10.2119/2008-00004.ray)

  • Scher HI, Beer TM, Higano CS, et al. 2010 Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375 1437–1446. (https://doi.org/10.1016/s0140-6736(10)60172-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sinnesael M, Jardi F, Deboel L, et al. 2015 The androgen receptor has no direct antiresorptive actions in mouse osteoclasts. Mol Cell Endocrinol 411 198–206. (https://doi.org/10.1016/j.mce.2015.04.030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun P, Wang J, Zheng Y, et al. 2012 BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer. Dent Mater J 31 239–248. (https://doi.org/10.4012/dmj.2011-191)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun Y, Wu H, Wang W, et al. 2019 Translational status of biomedical Mg devices in China. Bioactive Mater 4 358–365. (https://doi.org/10.1016/j.bioactmat.2019.11.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Thu HE, Mohamed IN, Hussain Z, et al. 2017 Dihydrotestosterone, a robust promoter of osteoblastic proliferation and differentiation: understanding of time-mannered and dose-dependent control of bone forming cells. Iran J Basic Med Sci 20 894–904. (https://doi.org/10.22038/IJBMS.2017.9111)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tran C, Ouk S, Clegg NJ, et al. 2009 Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324 787–790. (https://doi.org/10.1126/science.1168175)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tsai MY, Shyr CR, Kang HY, et al. 2011 The reduced trabecular bone mass of adult ARKO male mice results from the decreased osteogenic differentiation of bone marrow stroma cells. Biochem Biophys Res Commun 411 477–482. (https://doi.org/10.1016/j.bbrc.2011.06.113)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu Y, Xiang Y, Fang J, et al. 2019 The influence of the stiffness of GelMA substrate on the outgrowth of PC12 cells. Biosci Rep 39 BSR20181748. (https://doi.org/10.1042/bsr20181748)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang J, Zhang L, Ding Q, et al. 2023 Flavonoid-loaded biomaterials in bone defect repair. Molecules 28 6888. (https://doi.org/10.3390/molecules28196888)

  • Yatsu T, Kusakabe T, Kato K, et al. 2018 Selective androgen receptor modulator, YK11, up-regulates osteoblastic proliferation and differentiation in MC3T3-E1 cells. Biol Pharm Bull 41 394–398. (https://doi.org/10.1248/bpb.b17-00748)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yin B, Ma Q, Song C, et al. 2021 Exosome-derived noncoding RNAs as a promising treatment of bone regeneration. Stem Cells Int 2021 1–8. (https://doi.org/10.1155/2021/6696894)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yue K, Trujillo-de Santiago G, Alvarez MM, et al. 2015 Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels. Biomaterials 73 254–271. (https://doi.org/10.1016/j.biomaterials.2015.08.045)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang XY, Chen YP, Han J, et al. 2019 Biocompatiable silk fibroin/carboxymethyl chitosan/strontium substituted hydroxyapatite/cellulose nanocrystal composite scaffolds for bone tissue engineering. Int J Biol Macromol 136 1247–1257. (https://doi.org/10.1016/j.ijbiomac.2019.06.172)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang J, Jiang Y, Shang Z, et al. 2021 Biodegradable metals for bone defect repair: a systematic review and meta-analysis based on animal studies. Bioactive Mater 6 4027–4052. (https://doi.org/10.1016/j.bioactmat.2021.03.035)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhao Y, He J, Qiu T, et al. 2022 Epigenetic therapy targeting bone marrow mesenchymal stem cells for age-related bone diseases. Stem Cell Res Ther 13 201. (https://doi.org/10.1186/s13287-022-02852-w)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhou B, Jiang X, Zhou X, et al. 2023 GelMA-based bioactive hydrogel scaffolds with multiple bone defect repair functions: therapeutic strategies and recent advances. Biomater Res 27 86. (https://doi.org/10.1186/s40824-023-00422-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu M, Wang Y, Ferracci G, et al. 2019 Gelatin methacryloyl and its hydrogels with an exceptional degree of controllability and batch-to-batch consistency. Sci Rep 9 6863. (https://doi.org/10.1038/s41598-019-42186-x)

    • PubMed
    • Search Google Scholar
    • Export Citation