Other ECM molecules, such as OPN, OCN, and DMP1, can regulate the proliferation of MSCs and osteogenesis.  |  Sclerostin is an important inhibitor of WNT/β-catenin signaling and regulates osteoblast matrix generation. 2009;15:1334–1348. However, many such novel materials suffer from shortcomings such as poor biocompatibility, low osteoinductivity, and high immunogenicity. It has been reported that periostin may interact directly with sclerostin and promotes Wnt signaling inhibited by sclerostin (Bonnet et al., 2016). Osteoblasts have bound and soluble forms of receptor activator of nuclear-factor kappa-β ligand (RANKL), a key factor needed for osteoclast differentiation. 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. Int J Mol Sci. 132, 1–8. doi: 10.1128/MCB.00012-19, Zoch, M. L., Clemens, T. L., Riddle, R. C. (2016). (2011). This is especially true for large bones, where the missing tissue is larger than the spontaneous healing ability of osteoblasts (El-Rashidy et al., 2017; Fabris et al., 2018). The RGD sequence of OPN and BSP interact with αvβ3 integrin initiate osteoclast adhesion to bone matrix and formation of actin ring of polarized osteoclasts, which is crucial for bone development. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Part B. Rev. These results suggest that, unlike TSP1, TSP2 may act as an inhibitor of MSCs proliferation and a promoter of differentiation by regulating the mechanism of collagen fibrillogenesis. Scaffolds for Bone Tissue Engineering: State of the art and new perspectives. Trauma, fractures, congenital disease, or tumors can cause bone defects that are challenging to heal. doi: 10.2174/138161209787846739. Basal membrane : this membrane, generally considered part of the epith… Because of their good proliferation ability and capacity for osteogenic differentiation. Osteoclasts, are multinucleated cells formed from the fusion and differentiation of monocyte/macrophage precursors, involve in bone resorption. *Correspondence: Yong-Guang Gao, gaoyongguang@nwpu.edu.cn; Airong Qian, qianair@nwpu.edu.cn, †These authors have contributed equally to this work, Front. J. 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. Mater. Bone Miner. Osteoclasts secrete osteopontin into resorption lacunae during bone resorption. Matrix Biol. Therefore, decorin and biglycan mediate the proper sequestration of TGF-β and play a vital role in regulating the survival and growth of BMSCs (Bi et al., 2005). Obviously, MGP is responsible for disrupting bone formation and inhibiting mineralization. Cell Commun. One important group of bone ECM proteins contains γ-carboxyglutamic acid (Gla), a specific modified glutamic acid produced by a vitamin K-dependent post-translational modification. If there is no substrate, osteoblasts synthesize a matrix that is only organized in the short range. Thus, BSP is vital in the regulation of osteoblast differentiation and initiation of matrix mineralization in bone tissue (Marinovich et al., 2016). Matrix Gla Protein Promotes the Bone Formation by Up-Regulating Wnt/beta-Catenin Signaling Pathway. (2019). doi: 10.1016/j.matbio.2015.12.001, Kaipatur, N. R., Murshed, M., McKee, M. D. (2008). (2005). J. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. In this review, we briefly introduce the inorganic and organic ECM of bone tissue (Table 1), including collagenous and non-collagenous proteins, and summarize the effects of the ECM on osteoblast-lineage cells, including MSCs, osteoblasts, and osteocytes, and osteoclasts. (pink-brown stain). 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). The inter- and intra-chain crosslinks of collagen are key to its mechanical properties, which maintain the polypeptide chains in a tightly organized fibril structure. However, this approach is limited by the available sources of grafts and secondary damage at the donor site. The role of bone sialoprotein in the tendon-bone insertion. Serrano-Bello J, Cruz-Maya I, Suaste-Olmos F, González-Alva P, Altobelli R, Ambrosio L, Medina LA, Guarino V, Alvarez-Perez MA. Alcorta-Sevillano N, Macías I, Infante A, Rodríguez CI. The bone resorption process reduces OCN's affinity for hydroxyapatite, thereby enhance the release of OCN into circulation. Med. (2015). Sci. Moreover, TSP1-null mice show the increased bone mass and cortical bone size, and the differentiation of osteoblast is promoted, which is partly by activating latent TGF-β (Amend et al., 2015). Bioph. Common ECM-modified scaffold designs use a single or a combination of components of the ECM or apply a coating combined with biomaterials to produce scaffolds. Matrix Gla protein inhibition of tooth mineralization. A small amount of type III collagen is also found in collagen fibrils of bone. Notably, the addition of BMP-2 led to almost complete healing of bone defects (Kim et al., 2015). doi: 10.1089/ten.tea.2017.0179, Tavafoghi, M., Cerruti, M. (2016). Acharya, B., Chun, S. Y., Kim, S. Y., Moon, C., Shin, H. I., Park, E. K. (2012). In MSCs, TSP1 inhibits MSCs osteogenesis with decreased expression of Runx2 and ALP expression. Finally, it must allow the gradual integration into the host tissue during the healing process, allowing it to bear normal loads (Mishra et al., 2016; Roseti et al., 2017). By contrast, OPN can inhibit the process of osteoblast osteogenesis through inhibition of BMP-2, and act as a mineralization inhibitor of osteoblast in a phosphate-dependent manner (Huang et al., 2004; Singh et al., 2018). Sci. Int. Decellularized Adipose Tissue Hydrogel Promotes Bone Regeneration in Critical-Sized Mouse Femoral Defect Model. J. Dent. This extracellular matrix is made of: Organic components, being mostly type 1 collagen. 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). Tissue Eng. doi: 10.1016/j.matbio.2016.03.003, Bi, Y. M., Stuelten, C. H., Kilts, T., Wadhwa, S., Iozzo, R. V., Robey, P. G., et al. Consequently, such materials can effectively support bone regeneration and guide tissue reconstruction. The patients showed bony healing and new bone formation in the defect site (Govender et al., 2002; Calori et al., 2008). Consistent with that of OPN, OCN, which is produced by osteoblast, is considered as an inhibitor of bone mineralization. (2016). 432, 75–82. Bone Res. However, due to the complexity and dynamics of its components, there has been no systematic analysis of the components of the ECM secreted by cells or tissues, and it is not clear if decellularized ECM can completely match the biochemical imprint of the native bone ECM. Integrin-matrix combination is vital for podosome formation on osteoclasts. Autologous cells grown aseptically in vitro can be used to produce a cell-derived decellularized ECM avoiding the disadvantages of a tissue-derived decellularized ECM. Bioeng. doi: 10.1016/j.msec.2017.05.017, Rosset, E. M., Bradshaw, A. D. (2016). Calcif. (1997). Bone cells (osteoblasts, osteocytes and odontoblasts) are the major source of MEPE. R-spondin2 promotes osteoblastogenesis in vitro and bone mass in vivo, supporting its vital role in osteoblastogenesis and bone development (Knight et al., 2018). J. Nanosci. 9 Front. MEPE is synchronized with DMP1 and differentially regulates bone remodeling by mechanical loading. The animal extracellular matrix E. 41, 247–251. DMP1 and MEPE, thus, appear as key regulators of matrix mineralization and phosphate metabolism. 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). 437, 63–74. 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). SLRPs are secreted extracellular proteins that interact with cell surface receptors and cytokines to regulate both normal and pathological cellular behaviors. doi: 10.1016/j.jsb.2010.11.014, Kim, I. G., Hwang, M. P., Du, P., Ko, J., Ha, C. W., Do, S. H., et al. Hydrogels are unique model systems that can be used to determine interactions between cells and the bone matrix. Growth plate extracellular matrix-derived scaffolds for large bone defect healing. doi: 10.1016/j.actbio.2017.08.030, Fabris, A. L. D., Faverani, L. P., Gomes-Ferreira, P. H. S., Polo, T. O. Engineering Perspectives in Tissue Engineering - Preface. Stem cells are receiving increasing attention in regenerative medicine, including bone regeneration. Ideally, the scaffold material should mimic the characteristics of natural bone, providing a suitable biochemical environment and biomechanical support for the adhesion, migration, proliferation, osteogenic differentiation, and angiogenesis of seed cells on the scaffold. Synergistic Effects of Beta Tri-Calcium Phosphate and Porcine-Derived Decellularized Bone Extracellular Matrix in 3D-Printed Polycaprolactone Scaffold on Bone Regeneration. Osteogenic differentiated MSCs (OMSCs) and ECs were seeded into a nano‐HA/polyurethane (n‐HA/PU) scaffold at a ratio of 0.5/1.5, was more effective for bone repair in rat condylar femoral defects than OMSC scaffold and scaffold alone. Res. Med. Biol. hydrated gel. Rep-Uk 7, 12627. doi: 10.1038/s41598-017-12651-6, Kumar, S., Stokes, J.A. B. Appl. Importantly, bone tissue developed into the interior of the scaffold. 143, 281–296. Newly formed bones undergo physiological remodeling mediated by osteoclasts (Acharya et al., 2012). 30, 106–115. (2018). Bonelike® has a similar chemical and structural composition of human bone. Different components and contents of ECM modified with biomaterial-based scaffold, and further modified with stem cells and structure processing to mimic the natural biomaterials. Bone Miner. (2012). doi: 10.3109/14653249.2010.548379, Rentsch, C., Rentsch, B., Heinemann, S., Bernhardt, R., Bischoff, B., Forster, Y., et al. Res. B. contains collagen and minerals and has a high proportion of calcium phosphate crystals (hydroxyapatite) are correct. Cancers (Basel). ECM is not … Beyond that, porcine small intestinal submucosa (SIS) ECM was combined with true bone ceramic (TBC) and mineralized, to fabricate the tissue-derived ECM scaffold mSIS/TBC. Mater. doi: 10.1590/1678-7757-2016-0531, Finkelman, R. D., Butler, W. T. (1985). Cancer 8, 212–226. B., Santiago-Junior, J. F., Okamoto, R. (2018). Moreover, MEPE interacts with DMP1 and PHEX to affect FGF23 expression, thereby regulating phosphate, mineralization, and bone turnover (Zelenchuk et al., 2015). The non-collagenous proteins can be classified into four groups: γ-carboxyglutamate-containing proteins, proteoglycans, glycoproteins, and small integrin-binding ligands N-linked glycoproteins (SIBLINs) (Paiva and Granjeiro, 2017). Therefore, the types and amounts of bioactive molecules need to be further studied. Sci. doi: 10.1016/j.biomaterials.2015.01.054, Kim, J. Y., Ahn, G., Kim, C., Lee, J. S., Lee, I. G., An, S. H., et al. B. Asporin competes with decorin for collagen binding, binds calcium and promotes osteoblast collagen mineralization. doi: 10.1016/j.injury.2008.08.011, Campos, J. M., Sousa, A. C., Caseiro, A. R., Pedrosa, S. S., Pinto, P. O., Branquinho, M. V., et al. (A) ECM-modified biomaterials scaffold. Finally, the application of ECM-based scaffold for bone regeneration in bone tissue engineering is reviewed. Part of ECM protein not only regulates collagen fibrillogenesis but is required for osteoblast lineage progression, which ultimately affects mineralization. The organization of the osteocyte network mirrors the extracellular matrix orientation in bone. HHS The bone matrix comprises organic (40%) and inorganic compounds (60%). (2017). In mice, global knockout of TSP-1, -3, and -5 can cause severe abnormalities in skeletal development (Delany and Hankenson, 2009). Appearance of dentin gamma-carboxyglutamic acid-containing proteins in developing rat molars in vitro. 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). With experiments in vivo, Delany et al. 148, 203–303. This means that in addition to the different components of modified ECM to affect the cell behaviors in bone regeneration, different ECM contents also play different roles. Therefore, SLRPs play an essential role to maintain bone homeostasis. Collagen is produced during the mineralization of tissue and acts as a template for the deposition of HA (Tavafoghi and Cerruti, 2016). The structure of the extracellular matrix differs in composition between tissue types but is essentially made up of collagen fibers, proteoglycans and multiadhesive matrix proteins that are secreted by cells. Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts. demonstrated that nanofibrous HA/chitosan (nHAp/CTS) scaffolds seeded with MSCs were superior to membranous HAp/CTS in a rat model of cranial bone defect regeneration. Therefore, ECs in OMSC/EC‐scaffold plays an important role in bone formation and vascularization (Li et al., 2019). doi: 10.1042/BJ20090542, Kattimani, V., Lingamaneni, K. P., Yalamanchili, S., Mupparapu, M. (2019). The OECMS contained TGF-β and BMP2, leading to increased osteoinduction and osteoconduction (Onishi et al., 2018). Res. Use of eggshell-derived nano-hydroxyapatite as novel bone graft substitute-A randomized controlled clinical study. Moreover, the deficiency of biglycan disrupts the ability to produce BMSCs, and also attenuates it's normal metabolic activity. Cell Rep. 21, 2585–2596. doi: 10.22203/eCM.v033a10, Delany, A. M., Hankenson, K. D. (2009). Nanotechnol. doi: 10.1177/00220345850640070301, Fonseca, H., Moreira-Goncalves, D., Coriolano, H. J., Duarte, J. 13, 1544–1558. Matrix Biol. Collagen type I coating stimulates bone regeneration and osteointegration of titanium implants in the osteopenic rat. Except for collagen, controlled proportions of HA together with modified calcium phosphate, TCP, and ionic species to form Bonelike®, which can be used in non-critical bone defects treatment. Bioinspired Collagen-Apatite Nanocomposites for Bone Regeneration. A. 120, 6555–6569. A HA modified PCL/HA composite had better biocompatibility for hMSCs cells with higher proliferation and osteogenic potential, compared to neat PCL. B., Hankenson, K. D. (2010). Collagen type I degradation fragments act through the collagen receptor LAIR-1 to provide a negative feedback for osteoclast formation. B. J. BioMed. Annu. 7, 211. doi: 10.3389/fbioe.2019.00211, Moorehead, C., Prudnikova, K., Marcolongo, M. (2019). doi: 10.1007/s00223-015-9985-5, Sartori, M., Giavaresi, G., Parrilli, A., Ferrari, A., Aldini, N. N., Morra, M., et al. In the clinical study, the absorbable collagen sponge scaffold contains bone-stimulating agents, such as rhBMP-2, rhBMP-7, and PRP, to treat long bone defects and fracture of the patient. doi: 10.1002/jbmr.245, Bouleftour, W., Juignet, L., Verdiere, L., Machuca-Gayet, I., Thomas, M., Laroche, N., et al. Keratocan is expressed by osteoblasts and can modulate osteogenic differentiation. It is mainly synthesized by osteoblasts before the mineralization process (Mansour et al., 2017). Med. Front. Cell Biol. It has the advantage of maintaining ECM components, providing the original geometry and flexibility of the tissue, while also offering inherently low immunogenicity (Hoshiba et al., 2016). Bradshaw, A. I., Gu, X. S. ( 2016 ) can sense and respond external. Cancer Metastases to bone: Concepts, mechanisms, and cytokines—which interact to produce engineered constructs... 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