In silico analysis to reveal underlying trans differentiation mechanism of Mesenchymal Stem Cells into Osteocytes

Muhammad Shahid Javaid, Haiba Kaul, Numan Fazal, Faiza Yaqub, Nadia Naseer, Muzaffar Hanif, Noreen Latief

Abstract


Background: Bone is a mineralized dynamic tissue, helps to protect and support the body. Osteoarthritis damages the cartilage and is responsible for the degeneration of the bone. Many cell-based therapies are available to repair the damage however, the non-availability of autologous cells and slows healing during regeneration of the damaged bone present major constraints. Hence, there is a need to search for a convenient and easily available cell source that can not only be used to repair the bone but can also enhance its regenerative potential. β-glycerophosphate, dexamethasone, and L-ascorbic-2-phosphate can differentiate mesenchymal stem cells (MSCs) into osteocytes. So far, the interaction of these compounds with osteocytes-specific proteins has not been studied. In this study, in silico analysis was performed to investigate the interaction of proteins with osteocytes specific compounds at the amino acids level.

Methods: 3D structures of Dexamethasone and L-ascorbic-2-phosphate (ascorbic acid) were drawn using Molecular Operating Environment (MOE). Then absorption, distribution, metabolism, and excretion (ADME) analysis was achieved using an online tool of "Swiss Packageâ€. By Ramachandran plot, the predicted model of ALPL, MMP13, Osteonectin, and RunX2 proteins were evaluated. Then docking of these proteins with Dexamethasone and L-ascorbic-2-phosphate was performed.

Results: L-ascorbic-2-phosphate and Dexamethasone docked within the binding pockets of ALPL, RunX2, MMP13, and Osteonectin proteins, expressed in the bone cells. These compounds also showed good drug-likeness and pharmacokinetics properties.

Conclusion: It is concluded that β-glycerophosphate, dexamethasone, and L-ascorbic-2-phosphate are novel substrates for osteogenic differentiation. These compounds could increase the healing and regenerative potential of bone cells by enhancing the expression of osteocytes specific proteins.

Keywords: Bone; Osteoarthritis; β-glycerophosphate; Dexamethasone; L-ascorbic-2-phosphate; Docking; Differentiation; Mesenchymal stem cells (MSCs); Osteonectin 

Editorial Note on Version of Record

This article has been corrected. See https://doi.org/10.62940/als.v13i0.4210 for more information.


Full Text:

PDF

References


Phan T, Xu J, Zheng M. Interaction between osteoblast and osteoclast: impact in bone disease. Histology and histopathology, (2004); 19(4): 1325-44.

Sims NA, Walsh NC. Intercellular cross-talk among bone cells: new factors and pathways. Current osteoporosis reports, (2012); 10(2): 109-117.

Stains JP, Civitelli R. Gap junctions in skeletal development and function. Biochimica et Biophysica Acta (BBA)-Biomembranes, (2005); 1719(1-2): 69-81.

Watkins M, Grimston SK, Norris JY, Guillotin B, Shaw A, et al. Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Molecular biology of the cell, (2011); 22(8): 1240-1251.

Del Fattore A, Teti A, Rucci N. Bone cells and the mechanisms of bone remodelling. Front Biosci (Elite Ed), (2012); 42302-2321.

Neve A, Corrado A, Cantatore FP. Osteoblast physiology in normal and pathological conditions. Cell and tissue research, (2011); 343(2): 289-302.

Clarke B. Normal bone anatomy and physiology. Clinical journal of the American Society of Nephrology, (2008); 3(Supplement 3): S131-S139.

Pajevic PD. Regulation of bone resorption and mineral homeostasis by osteocytes. Ibms Bonekey, (2009); 663.

Komori T. Functions of the osteocyte network in the regulation of bone mass. Cell and tissue research, (2013); 352(2): 191-198.

Akkiraju H, Nohe A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. Journal of developmental biology, (2015); 3(4): 177-192.

Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature, (2005); 434(7033): 644-648.

Hochberg MC (2002) Prevention of lower limb osteoarthritis: data from the Johns Hopkins Precursors Study. The many faces of Osteoarthritis: Springer. pp. 31-37.

Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthritis and cartilage, (2004); 1239-44.

Altindag O, Erel O, Aksoy N, Selek S, Celik H, et al. Increased oxidative stress and its relation with collagen metabolism in knee osteoarthritis. Rheumatology international, (2007); 27(4): 339-344.

Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. The Lancet, (2002); 359(9321): 1929-1936.

Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone, (2008); 42(4): 606-615.

Chen Q, Shou P, Zheng C, Jiang M, Cao G, et al. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death & Differentiation, (2016); 23(7): 1128-1139.

Dai F, Zhang F, Sun D, Zhang Z, Dong S, et al. CTLA4 enhances the osteogenic differentiation of allogeneic human mesenchymal stem cells in a model of immune activation. Brazilian Journal of Medical and Biological Research, (2015); 48629-636.

Javaid MS, Latief N, Ijaz B, Ashfaq UA. Epigallocatechin gallate as an anti-obesity therapeutic compound: An in silico approach for structure-based drug designing. Natural product research, (2018); 32(17): 2121-2125.

Oshina H, Sotome S, Yoshii T, Torigoe I, Sugata Y, et al. Effects of continuous dexamethasone treatment on differentiation capabilities of bone marrow-derived mesenchymal cells. Bone, (2007); 41(4): 575-583.

Boskey AL, Guidon P, Doty SB, Stiner D, Leboy P, et al. The mechanism of βâ€glycerophosphate action in mineralizing chick limbâ€bud mesenchymal cell cultures. Journal of Bone and Mineral Research, (1996); 11(11): 1694-1702.

Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. Journal of Biological Chemistry, (2005); 280(39): 33132-33140.

Hamidouche Z, Haÿ E, Vaudin P, Charbord P, Schüle R, et al. FHL2 mediates dexamethasoneâ€induced mesenchymal cell differentiation into osteoblasts by activating Wnt/βâ€catenin signalingâ€dependent Runx2 expression. The FASEB Journal, (2008); 22(11): 3813-3822.

Hong D, Chen H-X, Xue Y, Li D-M, Wan X-C, et al. Osteoblastogenic effects of dexamethasone through upregulation of TAZ expression in rat mesenchymal stem cells. The Journal of steroid biochemistry and molecular biology, (2009); 116(1-2): 86-92.

Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, et al. TAZ: a novel transcriptional coâ€activator regulated by interactions with 14â€3â€3 and PDZ domain proteins. The EMBO journal, (2000); 19(24): 6778-6791.

Hong J-H, Hwang ES, McManus MT, Amsterdam A, Tian Y, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science, (2005); 309(5737): 1074-1078.

Phillips JE, Gersbach CA, Wojtowicz AM, García AJ. Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation. Journal of cell science, (2006); 119(3): 581-591.

Vater C, Kasten P, Stiehler M. Culture media for the differentiation of mesenchymal stromal cells. Acta biomaterialia, (2011); 7(2): 463-477.

Yiu GK, Chan WY, Ng S-W, Chan PS, Cheung KK, et al. SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. The American journal of pathology, (2001); 159(2): 609-622.

Delany AM, Kalajzic I, Bradshaw AD, Sage EH, Canalis E. Osteonectin-null mutation compromises osteoblast formation, maturation, and survival. Endocrinology, (2003); 144(6): 2588-2596.

Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nature reviews Molecular cell biology, (2007); 8(3): 221-233.




DOI: https://doi.org/10.62940/als.v8i4.1297

Refbacks

  • There are currently no refbacks.