Role and Application of Wnt/β-catenin Signaling Pathway in Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells

Linlang Xu; Ziheng Zeng

doi:10.54097/ddt58253

Authors

Linlang Xu
Ziheng Zeng

DOI:

https://doi.org/10.54097/ddt58253

Keywords:

Wnt/β-catenin, osteogenic differentiation, bone marrow mesenchymal stem cells.

Abstract

The Wnt/β-catenin signaling pathway is a crucial signaling mechanism in multicellular organisms, regulating a variety of cellular behaviors. It acts a significant role in the differentiation of bone marrow mesenchymal stem cells (MSCs) into osteoblasts and in maintaining bone homeostasis. This involves promoting gene expression that is relevant and interacting with other pathways to boost osteogenic differentiation when inhibiting the differentiation of cartilage and adipocytes. This paper reviews the role of the MSCs' osteogenic differentiation and the Wnt/β-catenin signaling pathway, explores the relationship between abnormalities in this pathway and various skeletal diseases, and discusses The Wnt signaling pathway can potentially be targeted in order to create medicinal strategies for these conditions, offering new insights for the treatment of skeletal disorders.

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References

[1] Shu H S, Liu Y L, Tang X T, et al. Tracing the skeletal progenitor transition during postnatal bone formation. Cell Stem Cell, 2021, 28 (12): 2122 - 2136.

[2] Nusse R, Brown A, Papkoff J, et al. A new nomenclature for int-1 and related genes: The Wnt gene family. Cell, 1991, 64 (2): 231.

[3] Steinhart Z, Angers S. Wnt signaling in development and tissue homeostasis. Development, 2018, 145 (11): dev146589.

[4] Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science, 1991, 253 (5020): 665 – 669.

[5] Hu L, Chen W, Qian A, et al. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Research, 2024, 12 (1): 1 – 33.

[6] Takada R, Satomi Y, Kurata T, et al. Monounsaturated Fatty Acid Modification of Wnt Protein: Its Role in Wnt Secretion. Developmental Cell, 2006, 11 (6): 791 – 801.

[7] Tamai K, Semenov M, Kato Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature, 2000, 407 (6803): 530 – 535.

[8] Tsutsumi N, Hwang S, Hansen S, et al. Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for co-receptor discrimination. Proc Natl Acad Sci U S A, 2023, 120 (11): e2218238120.

[9] Liu J, Xiao Q, Xiao J, et al. Wnt/β-catenin Signalling: Function, Biological mechanisms, and Therapeutic Opportunities. Signal Transduction and Targeted Therapy, 2022, 7 (3): 3.

[10] Clevers H, Nusse R. Wnt/β-Catenin Signaling and Disease. Cell, 2012, 149 (6): 1192 – 1205.

[11] Hill T P, Später D, Taketo M M, et al. Canonical Wnt/β-Catenin Signaling Prevents Osteoblasts from Differentiating into Chondrocytes. Developmental Cell, 2005, 8 (5): 727 – 738.

[12] Glass D A, Bialek P, Ahn J D, et al. Canonical Wnt Signaling in Differentiated Osteoblasts Controls Osteoclast Differentiation. Developmental Cell, 2005, 8 (5): 751 – 764.

[13] Bennett C N, Longo K A, Wright W S, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proceedings of the National Academy of Sciences, 2005, 102 (9): 3324 – 3329.

[14] Albers J, Keller J, Anke Baranowsky, et al. Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin. Journal of Cell Biology, Rockefeller University Press, 2013, 200 (4): 537 – 549.

[15] Albers J, Schulze J, F. Timo Beil, et al. Control of bone formation by the serpentine receptor Frizzled-9. The Journal of Cell Biology, Rockefeller University Press, 2011, 192 (6): 1057 – 1072.

[16] Gong Y, Slee R B, Fukai N, et al. LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development. Cell, 2001, 107 (4): 513 – 523.

[17] Boyden L M, Mao J, Belsky J, et al. High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5. New England Journal of Medicine, 2002, 346 (20): 1513 – 1521.

[18] Itoh S, Saito T, Hirata M, et al. GSK-3α and GSK-3β Proteins Are Involved in Early Stages of Chondrocyte Differentiation with Functional Redundancy through RelA Protein Phosphorylation. Journal of Biological Chemistry, 2012, 287 (35): 29227 – 29236.

[19] Kugimiya F, Kawaguchi H, Ohba S, et al. GSK-3β Controls Osteogenesis through Regulating Runx2 Activity. C.-P. Heisenberg. PLoS ONE, 2007, 2 (9): e837.

[20] Gaur T, Lengner C J, Hovhannisyan H, et al. Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression. Journal of Biological Chemistry, 2005, 280 (39): 33132 – 33140.

[21] Byun M R, Hwang J-H, Kim A R, et al. Canonical Wnt signalling activates TAZ through PP1A during osteogenic differentiation. Cell Death & Differentiation, 2014, 21(6): 854 – 863.

[22] Zhao X, Xie L, Wang Z, et al. ZBP1 (DAI/DLM-1) promotes osteogenic differentiation while inhibiting adipogenic differentiation in mesenchymal stem cells through a positive feedback loop of Wnt/β-catenin signaling. Bone Research, 2020, 8 (1): 196 - 203.

[23] Hang K, Ying L, Bai J, et al. Knockdown of SERPINB2 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the Wnt/β-catenin signalling pathway. Stem Cell Research & Therapy, 2021, 12 (1): 235 - 243.

[24] Kang S, Bennett C N, Gerin I, et al. Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ. Journal of Biological Chemistry, 2007, 282 (19): 14515 – 14524.

[25] Karner C M, Long F. Wnt signaling and cellular metabolism in osteoblasts. Cellular and Molecular Life Sciences, 2016, 74 (9): 1649 – 1657.

[26] Kovács B, Vajda E, Nagy E E. Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis. International Journal of Molecular Sciences, 2019, 20 (18): 4653.

[27] Varelas X, Miller B W, Sopko R, et al. The Hippo Pathway Regulates Wnt/β-Catenin Signaling. Developmental Cell, 2010, 18 (4): 579 – 591.

[28] Zhu S, Chen W, Masson A, et al. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discovery, Springer Nature, 2024, 10 (1): 113 - 121.

[29] Adam S, Simon N, Steffen U, et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Science Translational Medicine, American Association for the Advancement of Science, 2020, 12 (530): 157 - 172.

[30] Stegen S, Stockmans I, Moermans K, et al. Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin. Nature Communications, 2018, 9 (1): 386.

[31] Kamiya N, Ye L, Kobayashi T, et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development, 2008, 135 (22): 3801 – 3811.

[32] Esen E, Chen J, Karner Courtney M, et al. WNT-LRP5 Signaling Induces Warburg Effect through mTORC2 Activation during Osteoblast Differentiation. Cell Metabolism, 2013, 17 (5): 745 – 755.

[33] Fahiminiya S, Majewski J, Mort J, et al. Mutations in WNT1 are a cause of osteogenesis imperfecta. Journal of Medical Genetics, 2013, 50 (5): 345 – 348.

[34] Xia C, Wang P, Fang L, et al. Activation of β‐catenin in Col2 ‐expressing chondrocytes leads to osteoarthritis‐like defects in hip joint. Journal of Cellular Physiology, 2019, 234 (10): 18535 – 18543.

[35] Tong W, Zeng Y, Chow D H K, et al. Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade. Annals of the Rheumatic Diseases, 2019, 78 (4): 551 – 561.

[36] Zhu Z, Bai X, Wang H, et al. A study on the mechanism of Wnt inhibitory factor 1 in osteoarthritis. Archives of Medical Science, 2020, 16 (4): 898 – 906.

[37] Li X, Grisanti M, Fan W, et al. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. Journal of Bone and Mineral Research, Oxford University Press, 2011, 26 (11): 2610 – 2621.

[38] Yin C, Tian Y, Yu Y, et al. miR-129-5p Inhibits Bone Formation Through TCF4. Frontiers in Cell and Developmental Biology, 2020, 8: 432.

[39] Ominsky M S, Li C, Li X, et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. Journal of Bone and Mineral Research, 2011, 26 (5): 1012 – 1021.

[40] Weng L-H, Wang C-J, Ko J-Y, et al. Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis & Rheumatism, 2010, 62 (5): 1393 – 1402.