Thus, this organized surface is used by osteoblasts to deposit mechanically stable and correctly structured bone tissue (Kerschnitzki et al., 2011). doi: 10.1016/j.matbio.2016.07.001. The bone resorption process reduces OCN's affinity for hydroxyapatite, thereby enhance the release of OCN into circulation. doi: 10.3109/14653249.2010.548379, Rentsch, C., Rentsch, B., Heinemann, S., Bernhardt, R., Bischoff, B., Forster, Y., et al. 78, 1246–1262. J. Taiwan Inst. Therefore, the dynamic assembly of bone collagen contributes greatly to the encapsulation and mineralization of osteocytes in bone matrix (Shiflett et al., 2019). 22, 193–207. The outermost layer of bone is composed of densely packed cortical bone, while the interior and ends of bone are made up of trabecular bone (gray region). Thrombospondin-2 and SPARC/osteonectin are critical regulators of bone remodeling. doi: 10.1016/j.bone.2009.08.058, PubMed Abstract | CrossRef Full Text | Google Scholar, Alford, A. I., Golicz, A. Bone 82, 42–49. See this image and copyright information in PMC. Synergistic Effects of Beta Tri-Calcium Phosphate and Porcine-Derived Decellularized Bone Extracellular Matrix in 3D-Printed Polycaprolactone Scaffold on Bone Regeneration. Osteoclasts, are multinucleated cells formed from the fusion and differentiation of monocyte/macrophage precursors, involve in bone resorption. In mice, deletion of TSP2 results in increased number and proliferation ability of MSC, and also characterized by delayed osteogenesis and increased adipogenesis (Hankenson et al., 2000). In mice, global knockout of TSP-1, -3, and -5 can cause severe abnormalities in skeletal development (Delany and Hankenson, 2009). Models to study the complex interactions between the bone matrix and metastatic cancer cells are limited. doi: 10.1166/jnn.2014.9127, Ramesh, N., Moratti, S. C., Dias, G. J. 94, 621–631. doi: 10.1128/MCB.00012-19, Zoch, M. L., Clemens, T. L., Riddle, R. C. (2016). Keywords: 96, 29–39. Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif. Osteoclasts are derived from a monocyte/macrophage lineage. doi: 10.1002/jbm.b.32648, Alford, A. I., Terkhorn, S. P., Reddy, A. (2015). Res. Sci. This might due to increased secretion of Alp and Col (Xie et al., 2016). Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts. eCollection 2020. doi: 10.1371/journal.pone.0131105, Cunniffe, G. M., Diaz-Payno, P. J., Ramey, J. S., Mahon, O. R., Dunne, A., Thompson, E. M., et al. Importantly, bone tissue developed into the interior of the scaffold. R00 CA178177/CA/NCI NIH HHS/United States, 4100072566/Pennsylvania State Department of Health, Lu P., Takai K., Weaver V.M., Werb Z. Extracellular Matrix Degradation and Remodeling in Development and Disease. Cell Proliferat. obtained electrospun microfibrous sheets by combining layers of a microfibrous mat composed of electrospun poly(L-lactic acid) (PLLA), gelatin–nanoHA matrix (GHA), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide called GHA-MFE. Rentsch et al. Increased marrow-derived osteoprogenitor cells and endosteal bone formation in mice lacking thrombospondin 2. They are widely expressed at different stages of skeletal tissue and act as a reinforcer of the Wnt/β-catenin signaling pathway through leucine-rich repeat-containing G-protein-coupled receptors 4, 5, and 6 (Lgr4/5/6). With experiments in vivo, Delany et al. The extracellular matrix of bone A. is entirely composed of proteoglycans. Table 1 The list of bone ECM components and their role in bone formation. Required adjustment of ionic concentrations and water removal from bone matrix are important details … doi: 10.1177/154405910808700907, Kalamajski, S., Aspberg, A., Lindblom, K., Heinegard, D., Oldberg, A. In recent years, bone tissue engineering has developed rapidly, providing a promising new approach for bone repair. Except for OCN and MGP, periostin is another abundantly expressed Gla-containing protein in bone. (2017). 106, 2046–2057. Small leucine-rich proteoglycans (SLRPs), such as biglycan, decorin, keratocan, and asporin, are important proteoglycans family in the bone. MGP also inhibits bone formation and MGP-null mice exhibit an osteopenic phenotype, suggesting that MGP plays a stronger role in bone absorption than in bone formation (Zhang Y. et al., 2019). Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. Orthop. (2017). J. The lack of type I collagen or mutation of collagen structure results in changes in the ECM, and thus significantly increases fracture risk (Fonseca et al., 2014). Cell-derived dECM, rich in collagen, matrix macromolecules, and growth factors, has good biocompatibility and biodegradability, making it beneficial for the proliferation and osteogenic differentiation of MSCs, and can be used as cell culture matrix for bone regeneration medicine. The growth plate is located in the metaphysis region and allows for longitudinal growth of bone. doi: 10.1007/s00198-011-1892-7, Mishra, R., Bishop, T., Valerio, I. L., Fisher, J. P., Dean, D. (2016). This review discusses the recent progress in the utilization of bone and cartilage dECM through applications as scaffolds, particles, and supplementary factors in bone and cartilage tissue engineering. Biosci. Res. Dental pulp stem cells and Bonelike((R)) for bone regeneration in ovine model. Liu and colleagues indicate that F-actin cytoskeleton and chromatin structure organized by EZH2-mediated H3K27me3 involves OPN-induced MSCs migration (Liu et al., 2018; Liu et al., 2019). doi: 10.2217/rme-2016-0042, Mizokami, A., Kawakubo-Yasukochi, T., Hirata, M. (2017). 97, 229–240. Bone scaffolds are usually made of biodegradable materials that are porous and effectively integrate seed cells, growth factors, and drugs, as well as provide mechanical support during the repair and regeneration of the damaged bone (Bose et al., 2012). However, this approach is limited by the available sources of grafts and secondary damage at the donor site. ECM is not … doi: 10.1016/j.celrep.2017.10.115, Dussold, C., Gerber, C., White, S., Wang, X. Y., Qi, L. X., Francis, C., et al. Among the organic components, type I collagen provides the tensile strength of bone. Acta Biomater. (2019). In conclusion, the application of ECM in bone formation and bone regeneration is full of opportunities and challenges. BSP is crucial for the synthesis of the ECM and HA nucleation activity. Mol. Role of Extracellular Matrix in Development and Cancer Progression. Thrombospondins (TSPs), which are classified as TSP1 through TSP5, are present in developing skeleton and bone and is expressed by osteoblasts. The promotion of bone regeneration by nanofibrous hydroxyapatite/chitosan scaffolds by effects on integrin-BMP/Smad signaling pathway in BMSCs. doi: 10.1016/j.actbio.2015.10.007, Yi, S., Ding, F., Gong, L. I., Gu, X. S. (2017). Glycoproteins contain covalently attached carbohydrate molecules on the protein chain in various combinations and positions. Therefore, the components and composition of decellularized ECM scaffolds, as well as the dynamic changes of ECM under different culture conditions should be further studied to make it more similar to the natural ECM composition. MSCs, osteoblasts, and osteocytes sense mechanical and biochemical signals from the ECM and respond to these signals by regulating their fate (Assis-Ribas et al., 2018). Additionally, it is difficult to precisely control the ECM components secreted by cells, so that they can be standardized and unified in mass production. Cold Spring Harb. Recently, it is demonstrated that the process by which osteocytes push type I collagen fibers outward from the center of the formed lacuna mediates osteocytes lacunae formation, which is accompanied by increased collagen deposition and collagen-fiber network compaction surround the lacunae. Other ECM molecules, such as OPN, OCN, and DMP1, can regulate the proliferation of MSCs and osteogenesis. doi: 10.1590/1678-7757-2016-0531, Finkelman, R. D., Butler, W. T. (1985). After 6 months, active bone formation can be detected in both callus and graft of the patient (Hesse et al., 2010). doi: 10.1016/j.mce.2015.12.014, Boraschi-Diaz, I., Mort, J. S., Bromme, D., Senis, Y. Vitamin K-dependent proteins involved in bone and cardiovascular health. Serrano-Bello J, Cruz-Maya I, Suaste-Olmos F, González-Alva P, Altobelli R, Ambrosio L, Medina LA, Guarino V, Alvarez-Perez MA. Different structures composed of type I collagen have different effects on the behavior of osteoblasts. (2003). It has long been understood to be the structural support for cells since its characteristics set the characteristics of the … The main function of collagens is mechanical support and to act as a scaffold for bone cells (Saito and Marumo, 2015). Even when using decellularized preparations of autologous or allogeneic tissue or cells cultured in vitro, the integrity and mechanical properties of the matrix components are preserved, while achieving low immunogenicity by removing cell-bound antigens. B. Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. J. Dent. Notably, the addition of BMP-2 led to almost complete healing of bone defects (Kim et al., 2015). 2015;65:20–31. Like cartilage, and other types of connective tissue, bone is made up of Cells and Extracellular matrix: Cells - which in bone are called osteoblasts and osteocytes, (osteo - bone). 36, 69–80. A better understanding of the role of bone ECM in guiding cellular behavior and tissue function is essential for its future applications in bone repair and regenerative medicine. (Liu et al., 2016). Knockout of MEPE in mice increases bone mass and trabecular density and shows abnormal cancellous bone. Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts. (2018). Tissue engineering utilizes the basic principles and methods of life sciences and engineering to create functional tissue substitutes in vitro, which can be used to repair tissue defects and replace the partial or total loss of organ function (Shafiee and Atala, 2017). Endocrinol. These fibrils interact with other collagenous and noncollagenous proteins to assemble the higher-order fibril bundles and fibers (Varma et al., 2016). Moreover, MEPE interacts with DMP1 and PHEX to affect FGF23 expression, thereby regulating phosphate, mineralization, and bone turnover (Zelenchuk et al., 2015). Once osteoclastogenesis is initiated, mono-nucleate osteoclast precursors fuse together to form multi-nucleate, mature osteoclasts. Inorganic components, including hydroxyapatite and other salts, such as calcium and phosphate. doi: 10.1139/bcb-2018-0263, Luo, G. B., Ducy, P., McKee, M. D., Pinero, G. J., Loyer, E., Behringer, R. R., et al. A small amount of type III collagen is also found in collagen fibrils of bone. Basal membrane : this membrane, generally considered part of the epith… Pharm. The ECM of each tissue type has a unique composition and topology during development (Frantz et al., 2010). (B) decellularized ECM scaffold obtained either from tissue in vivo or cultured cells in vitro by decellularization, which is a promising strategy to induce bone regeneration and has good clinical performance. DSPP is important for the mineralization of tooth dentin, and is consequently abundant in dentin tissue (Bouleftour et al., 2019). Like it? Enhanced bone tissue regeneration of a biomimetic cellular scaffold with co-cultured MSCs-derived osteogenic and angiogenic cells. Int. J. The extracellular matrix (ECM) is an intricate dynamic bio-environment with precisely regulated mechanical and biochemical properties. Obviously, MGP is responsible for disrupting bone formation and inhibiting mineralization. In bone remodeling, OPN regulates osteoclastogenesis and osteoclast activity, which contributes to bone formation and resorption (Singh et al., 2018). Rev. New insights into the biology of osteocalcin. (A) ECM-modified biomaterials scaffold. doi: 10.1042/BJ20090542, Kattimani, V., Lingamaneni, K. P., Yalamanchili, S., Mupparapu, M. (2019). HHS During bone regeneration, the homing of mesenchymal stem cells (MSCs), the formation of osteoblasts, extracellular matrix (ECM) and osteoid mineralization, and the formation of terminally differentiated osteocytes play an important role in bone formation (Wang et al., 2013). Calcif. ( a ) The…, Hydrogels as models of the bone matrix. In this review, we provide an overview of the function of various types of bone ECMs in bone tissue and their regulation roles in the behaviors of osteoblast-lineage cells and osteoclasts. Besides stem cells, endothelial cells (ECs) that contribute to vascularization can provide adequate nutritional support for the scaffold. 52-54, 95–112. NIH 2020 Jul;13(7):100789. doi: 10.1016/j.tranon.2020.100789. Interactions between minerals and matrix in teeth and bones, such as amino acids present in non-collagenous proteins, control HA formation. J. Tissue Eng. A., Mazharian, A., Komarova, S. V. (2018). 23, 1199–1212. 123, 4195–4200. doi: 10.2741/e795, Li, L. M., Li, J. D., Zou, Q., Zuo, Y., Cai, B., Li, Y. Mechanical properties of basement membrane in health and disease. This means that native decellularized bone transplantation has a broad application prospect in orthopedic surgery. It is mainly synthesized by osteoblasts before the mineralization process (Mansour et al., 2017). Moreover, they can synthesize copious amounts of extracellular matrix proteins such as collagen type IIIα1 and Vα1, α5 and β5 integrin chains, fibronectin, connective tissue growth factor, and transforming growth factor beta I (TGFβI) (Ren et al., 2011). BSP can promote bone resorption, and the migration of preosteoclast and mature osteoclasts is impaired in the absence of BSP (Boudiffa et al., 2010). Bone cells (osteoblasts, osteocytes and odontoblasts) are the major source of MEPE. doi: 10.1016/j.jtice.2009.10.002, Ueno, A., Miwa, Y., Miyoshi, K., Horiguchi, T., Inoue, H., Ruspita, I., et al. doi: 10.1111/cpr.12658, Lin, X., Zhao, C., Zhu, P., Chen, J., Yu, H., Cai, Y., et al. The stiffness of the surrounding matrix is one of the most important signals that regulate osteocyte behaviors, and changes in the stiffness of the ECM induce alterations in the cytoskeleton and cell morphology, as well as fibronectin, which leads to changes in paxillin and in turn affects the elongation of osteocyte gap junctions (Zhang D. M. et al., 2018). 60, 443–475. J. Struct. doi: 10.1016/j.jsb.2019.03.005, Mouw, J. K., Ou, G. Q., Weaver, V. M. (2014). BioMed. As an adhesion molecule, periostin promotes aggregation, adhesion, proliferation, and differentiation of osteoblasts by binding to cell surface receptors. 17, 331–340. Biochem. The matrix of bone contains collagen fibers and mineral deposits. E. 41, 247–251. 5, 17059. doi: 10.1038/boneres.2017.59, Garcia-Gareta, E., Coathup, M. J., Blunn, G. W. (2015). OPN is abundant in serine-, acidic, and aspartate-rich motif, which are potential phosphorylation sites involved in inhibiting mineralization. doi: 10.1146/annurev-med-102715-092331, Shamaz, B. H., Anitha, A., Vijayamohan, M., Kuttappan, S., Nair, S., Nair, M. B. Osteopontin is a negative regulator of proliferation and differentiation in MC3T3-E1 pre-osteoblastic cells. doi: 10.1016/j.actbio.2017.08.030, Fabris, A. L. D., Faverani, L. P., Gomes-Ferreira, P. H. S., Polo, T. O. dECM restricting its use. Cell Bio 15, 771–785. Rep-Uk 7, 12627. doi: 10.1038/s41598-017-12651-6, Kumar, S., Stokes, J.A. Scaffolds for Bone Tissue Engineering: State of the art and new perspectives. Compared to untreated defects, the scaffolds containing DPSCs significantly promoted the formation of correctly structured new bone and increased the volume of fibrous connective tissue and mineralized tissue, which was accompanied by the increased expression of osteogenic ALP and type I collagen (Chamieh et al., 2016). In addition to stimulating the maturation of osteoblasts and osteocytes, DMP1 can also affect the pluripotency of MSCs. doi: 10.3892/mmr.2018.8940, Wu, Y. 11, 571–587. Rep. 18, 3–15. With the development of tissue engineering technology, biomaterials manufactured using materials engineering, nanotechnology, and 3D printing been used to develop novel implants for bone regeneration. Sci. Periostin is mainly secreted by osteoblasts and their precursor cells in long bones and is also found in other organs, such as the heart (Wen et al., 2018). The dECM/PLGA/PLA scaffold significantly promoted new bone formation in a rat model of a calvarial bone defect. doi: 10.1146/, Knight, M. N., Karuppaiah, K., Lowe, M., Mohanty, S., Zondervan, R. L., Bell, S., et al. Therefore, ECs in OMSC/EC‐scaffold plays an important role in bone formation and vascularization (Li et al., 2019). Int. Cancers (Basel). Dev. (2014). Collagen … The organization of the osteocyte network mirrors the extracellular matrix orientation in bone. Mature, multi-nucleated osteoclast in vitro. Consequently, ECM release standards can be established to improve the quality of the graft. Articles, School of Dentistry, University of California, Los Angeles, United States, University of North Carolina at Chapel Hill, United States, University of California, Los Angeles, United States. View all Int. doi: 10.1016/j.bone.2014.10.007, Hoshiba, T., Chen, G. P., Endo, C., Maruyama, H., Wakui, M., Nemoto, E., et al. 15, 851–862. doi: 10.2106/00004623-200212000-00001, Hankenson, K. D., Bain, S. D., Kyriakides, T. R., Smith, E. A., Goldstein, S. A., Bornstein, P. (2000). 55, 106–116. However, TSP2 induces osteoclastogenesis through NFATc1, which is a RANKL-dependent pathway, accompanied by an increased RANKL/OPG ratio (Wang et al., 2019). 11:757. doi: 10.3389/fphar.2020.00757. Above all, different types, proportions, structures of ECM, and even different implanted cells can all affect the bone regeneration performance of the ECM-modified biomaterial scaffold, suggesting that there may be a set of elements of ECM that work in concert to guide bone regeneration. J. Advances in understanding the interactions between the bone ECM and bone metastatic cancer cells are necessary in order to both regulate and prevent metastatic cancer cell growth in bone. (2017). Osteoporos. It is composed predominantly of collagens, non-collagenous glycoproteins, hyaluronan and proteoglycans. Type III collagen null mice show affected osteoblast differentiation, consistent with decreased ALP activity, reduced osteogenic markers (OCN and BSP), and mineralization capacity (Volk et al., 2014). The extracellular matrix at a glance. J. Endodont. (2017). The decellularized ECM provides mechanical support for the regenerating cells and affects both their migration and cell fate decision (Gallie et al., 1989). Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. Nanotechnol. Pt A 24, 1034–1034. Calcif. In terms of influencing the maturation and function of osteoblasts, osteonectin and keratocan-null mice show fewer osteoblasts and decreased mineralized nodules in mutant cells (Igwe et al., 2011; Rosset and Bradshaw, 2016). (2019). Cancer 8, 212–226. In bone, ECMs are involved in regulating cell adhesion, proliferation, and responses to growth factors, differentiation, and ultimately, the functional characteristics of the mature bone. Cell Biol. used dECM from porcine bone to form 3D-printed PCL/β-TCP/bone dECM scaffolds, which promoted more new bone regeneration 6 weeks after repair of a rabbit calvarial defect in vivo. BiologyWise provides an in-depth study of the components, structure, and function of extracellular matrix. (2019). (2010). Asporin competes with decorin for collagen binding, binds calcium and promotes osteoblast collagen mineralization. Bone and bone mineral matrix are produced by osteoblasts and regulated by osteoclasts, which break down bone. Collagen Peptide Upregulates Osteoblastogenesis from Bone Marrow Mesenchymal Stem Cells through MAPK- Runx2. Pharmacol. 72, 341–351. The main inorganic components of the ECM are calcium-deficient apatite and trace elements. Extracellular Matrix Elasticity Regulates Osteocyte Gap Junction Elongation: Involvement of Paxillin in Intracellular Signal Transduction. TSP1 functions in the early stage of osteoclastogenesis, and TSP1 deficiency mice show decreased differentiation and activity of osteoclast. J. Mol. Therefore, SLRPs play an essential role to maintain bone homeostasis. Rev. MGP-deficient mice have reportedly exhibited premature bone mineralization, while mice with MGP overexpression in osteoblasts showed reduced mineralization of intramembranous bone and hypomineralized tooth dentin and cementum (Luo et al., 1997; Kaipatur et al., 2008). J. Mol. Sclerostin is an important inhibitor of WNT/β-catenin signaling and regulates osteoblast matrix generation. Pictured is one mature osteoclast differentiated with exogenous…, The bone matrix is manipulated to promote cancer growth. Orthop. Epub 2020 May 14. Bone 81, 112–121. In addition, Haj et al. Int. Fibrillogenesis starts from the interaction between type I and type V collagen, and then forms linear fibril. Zarrilli G, Businello G, Dieci MV, Paccagnella S, Carraro V, Cappellesso R, Miglietta F, Griguolo G, Guarneri V, Lo Mele M, Fassan M. Int J Mol Sci. 33, 130–142. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Bone Regeneration With Osteogenically Enhanced Mesenchymal Stem Cells and Their Extracellular Matrix Proteins. doi: 10.1002/jcb.27948, Carvalho, M. S., Silva, J. C., Cabral, J. M. S., da Silva, C. L., Vashishth, D. (2019b). This extracellular matrix is made of: Organic components, being mostly type 1 collagen. (2016). Biotechnol. (2019). The Wnt pathway is an important regulatory for bone formation. doi: 10.1002/jbmr.245, Bouleftour, W., Juignet, L., Verdiere, L., Machuca-Gayet, I., Thomas, M., Laroche, N., et al. The main inorganic constituent of hard tissues, such as bone and dentine, is hydroxyapatite (HA, Ca5(PO4)3OH) (Ramesh et al., 2018). Des. Oral. Bone Miner. doi: 10.1016/j.msec.2017.05.017, Rosset, E. M., Bradshaw, A. D. (2016). Trauma, fractures, congenital disease, or tumors can cause bone defects that are challenging to heal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). doi: 10.1177/0885328219863311, Kerschnitzki, M., Wagermaier, W., Roschger, P., Seto, J., Shahar, R., Duda, G. N., et al. Biochem. In the third month after implantation in patients, bone graft showed increased bone density and complete healing (Kattimani et al., 2019). These indicate that TSPs play a critical role in bone cell differentiation and maintaining bone mass. Bone quality: the determinants of bone strength and fragility. Bone ECM dynamically interacts with osteoblast-lineage cells and osteoclasts to regulate the formation of new bone during regeneration. 26, e20160531. Thus, the implant can be designed for improved bionic mechanical properties and stronger bone regeneration ability. R-spondins (roof plate-specific spondin) are a group of four secreted homologous glycoproteins (Rspo1-4) that belong to thrombospondin repeat containing matricellular protein family. D. J., Blunn, G. ( 2019 ) OMSC/EC‐scaffold plays an important inhibitor bone! On this GHA-MFE scaffold, providing stronger osteoinductive properties and mechanical support to... To musculoskeletal allografts: reviewed by the surrounding cells ( Ravindran et al., 2017 ) V. ( ). Mineral resorption in vitro its use vitro can be divided into two types that... Tsps play a critical role in osteoclast differentiation by ) by contrast, bone tissue engineering ( et! 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