Journal of Pharmaceutical and Biomedical Sciences

Water Extract of Bushen Huoxue Compound Improves Osteoporosis via Transcriptional and Translational Regulation of Key Factors in Notch and Wnt/b- Catenin Signaling Pathways in Ovariectomized Rats

Yingquan Xiong et al.

Abstract


Bushen Huoxue Compound is a Chinese herbal formula that shows promise in the treatment and prevention of osteoporosis (OP), but the mechanisms underlying its anti-osteoporotic effects are yet to be established. Here, we detect the influence of the
extract on several targets of the Notch and Wnt/b-catenin signaling pathways in bone tissue of ovariectomized rats as a model of OP with the aid of real-time PCR, western blot, and immunohistochemical staining. The water extract of BHC exerted a pronounced beneficial effect on OP rats and activated the Wnt/b-catenin pathway through regulating Wnt3a, Wnt10b protein, and glycogen synthesis kinase 3b (GSK-3b) mRNA. Furthermore, the BHC extract inhibited Jagged 1,2 protein and Notch 1,2 mRNA of the Notch signaling pathway. We detected simultaneous changes in the levels of a number of downstream transcripts, including increased runt-related transcription factor 2 (Runx 2) and decreased peroxisome proliferator-activated receptor b (PPARb ), which were closely correlated with the treatment effect. Based on the collective findings, we propose that the water extract of BHC regulates OP-associated factors through modulation of key transcripts and proteins in the Notch and Wnt/b-catenin pathways. Our results provide further mechanistic evidence supporting the clinical efficacy of BHC in the treatment of OP.

 


Keywords


Water extract of Bushen Huoxue Compound, Osteoporosis, Notch, Wnt/bcatenin

References


NIH consensus development panel on osteoporosis prevention, diagnosis, and therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785–795

Simas V, Hing W, Pope R, Climstein M. Effects of water-based exercise on bone health of middle-aged and older adults: a systematic review and meta-analysis. Open Access J Sports Med. 2017;8:39–60.

Maghbooli Z, Hossein-nezhad A, Jafarpour M, Noursaadat S, Ramezani M, Hashemian R, et al. Direct costs of osteoporosis-related hip fractures: protocol for a cross-sectional analysis of a national database. BMJ Open. 2017;7:e014898.

Tabatabaei-Malazy O, Salari P, Khashayar P, Larijani B. New horizons in treatment of osteoporosis. DARU J Pharm Sci. 2017;25:2.

Shu X, Zhang R, Peng K, Zhu X, Cai Y. The dose-and time-effect relationships of benefiting-bone capsule on proliferation of osteoblasts. Trad Chinese Med Mat (in Chinese). 2003;26:644–647.

Shu X, Zhang R, Zhu X, et al. The effect of Benefiting- bone Capsule drug serum on apoptosis of rat osteoclast and secrete tartrate-resistant acid phosphatase. Chinese J Pathophysiol (in Chinese). 2003;19:1234–1237.

Yang A, Zhang R, Lv H, et al. Bone histomorphometry index and volume change and therapeutical effect of Benefitingbone Capsule in ovariectomized rats. Chinese J Clin Rehab (in Chinese). 2005;9:165–167.

Ronghua Z, ji CK, Xiang LD, Feng ZX, Chang MX. A clinical study of Yigu capsule in treating postmenopausal osteoporosis. Chinese J Integ Trad Western Med. 2005;11:97–103.

Prakash S, Swaminathan U. b catenin in health: A review. J Oral Maxillofac Pathol. 2015;19:230–238.

Velázquez-Cruz R, García-Ortiz H, Castillejos-López M, et al. Wnt3a gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban mexican population: Findings of a pathway-based high-density single nucleotide screening. Age. 2014;36:1483–1492.

de Boer J, Siddappa R, Gaspar C, van Apeldoorn A, Fodde R, van Blitterswijk C. Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone. 2004;34: 818–826.

Ling L, Dombrowski C, Foong KM, Haupt LM, Stein GS, Nurcombe V, et al. Synergism between wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/akt/ runx2 pathway. J Biol Chem. 2010;285: 26233–26244.

Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, et al. Regulation of osteoblastogenesis and bone mass by wnt10b. Proc Natl Acad Sci USA. 2005;102:3324–3329.

Bennett CN, Ouyang H, Ma YL, et al. Wnt10b increases postnatal bone formation by enhancing osteoblast differentiation. J Bone Min Res. 2007;22:1924–1932.

Clevers H. Wnt/b-catenin signaling in development and disease. Cell. 2006;127:469–480.

MacDonald BT, Tamai K, He X. Wnt/b-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

Espinosa L, Ing lés-Esteve J, Aguilera C, et al. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003;278:32227–32235.

Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E. Notch1 impairs osteobiastic cell differention. J Endocrinology. 2003;144:5631–5639.

DevlinH, Ferguson MW. Compositional changes in rat femur following ovariectomy. Act Anat Basle. 1989;136:38–41.

Kalu DN. Evaluation of the pathogenesis of skeletal changes in ovariectomized rats. Endocrinology. 1984;115:507–512.

Chen Q, Shou P, Zheng C, et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?. Cell Death & Differentiation, 2016.

Campa VM, Gutiérrez-Lanza R, Cerignoli F. Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. J Cell Biol. 2008;183(1):129–141.

Nobta M, Tsukazaki T, Shibata Y, et al. CritBHCl regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1, 2 activated Notch 1 signaling. J Biol Chem. 2005;280(16):15842–15848.

Evans AG, Calvi LM. Notch signaling in the malignant bone marrow microenvironment: implications for a niche?based model of oncogenesis. Annals of the New York Academy of Sciences. 2015;1335(1):63–77.

Jung SR, Song NJ, Yang DK, et al. Silk proteins stimulate osteoblast differentiation by suppressing the Notch signaling pathway in mesenchymal stem cells. Nutr Res. 2013;33(2):162–170.

Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14(3):306–314.

Bai S, Kopan R, Zou w, et al. Notch 1 regulates osteoclastogenesis directly in osterolast precursors and indirectly via osteoblast lineage cells J. J Biol Chem. 2008;283(10):6509–6518.

Yanjie J, Jiping S, Yan Z, et al. Effects of Notch-1 signalling pathway on differentiation of marrow mesenchymal stem cells into neurons in vitro. Neuroreport. 2007;18:1443–1447.

Boopathy AV, Pendergrass KD, Che PL, et al. Oxidative stress-induced Notch 1 signaling promotes cardiogenic gene expression in mesenchymal stem cells. Stem Cell Res Ther. 2013;4(2):43.

Evans AG, Calvi LM. Notch signaling in the malignant bone marrow microenvironment: implications for a niche?based model of oncogenesis. Annals of the New York Academy of Sciences. 2015;1335(1):63–77.

Bai S, Kopan R, Zou W. NOTCH 1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem. 2008;283(10):6509–6518.

Lecarpentier Y, Claes V, Vallée A, et al. Interactions between PPAR gamma and the canonical Wnt/beta-catenin pathway in type 2 diabetes and colon cancer. PPAR research, 2017.

Abdallah BM, Jafari A, Zaher W, et al. Skeletal (stromal) stem cells: an update on intracellular signaling pathways controlling osteoblast differentiation. J Bone. 2015;70:28–36.

Velázquez-Cruz R, García-Ortiz H, Castillejos-López M, et al. Wnt3a gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban mexican population: Findings of a pathway-based high-density single nucleotide screening. Age. 2014;36(3):1483–1492.

Guo L, Li X, Tang QQ. Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) ?J. Journal of Biological Chemistry. 2015; 290(2):755–761.

Chen J, Long F. ??catenin promotes bone formation and suppresses bone resorption in postnatal growing mice. Journal of Bone and Mineral Research. 2013;28(5):1160–1169.

Shindo K, Kawashinma N, Sakamoto K, et al. Osteogenic differention of mesenchymal progenitor cells, Kusa is suppressed by Notch signaling. Exp Cell Res. 2003;290(2):370–380.

Sciaudone M, Gazzerro E, Priest L, et al. Notch 1 impairs osteobiastic cell differention. Endocrinology. 2003;144(12):5631–5639.

Kovall RA. More complicated than it looks: assembly of Notch pathway transcription complexes. Oncogene. 2008; 27(38):5099–5109.

Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237–255.

Grogan SP, Olee T, Hiraoka K, et al. Repression of chondrogenesis through binding of notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site. Arthritis Rheum. 2008;58(9):2754–2763.


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