143, 281–296. Moreover, the 1/3 ratio of MSCs/HUVECs has the best angiogenic effect on MSCs (Carvalho et al., 2019b). It is composed mainly of protein and includes collagens, elastin, reticulin, glycoproteins, proteoglycans, fibronectin, laminins … components of the extracellular matrix. Extracellular Matrix Alterations in Metastatic Processes. 105, 915–923. Forming an essential support structure for cells. doi: 10.3109/03008207.2010.546536, Jani, P. H., Gibson, M. P., Liu, C., Zhang, H., Wang, X., Lu, Y., et al. Cell Biol. (2011). Chem. J. (2015). 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). A., Chiu, Y. C., Lin, Y. H., Ho, C. C., Shie, M. Y., Chen, Y. W. (2019). As a result of the deletion of BSP in mice, cementum deposition is significantly reduced, and long bone length and cortical thickness, the rate of bone formation are also reduced. Biglycan is expressed during the process of cell proliferation and mineralization, while Decorin is continuously expressed starting from bone matrix deposition. 17, 331–340. Cell Biol. Moreover, MSCs derived from induced pluripotent stem cells (iPSC-MSCs) combined with HAp/Col/CTS nanofibers also had a good bone regeneration ability in mice cranial defects, with almost 2-fold higher bone density than either TCP, CTS or HAp/CTS scaffolds. Cell Mater. Int. J. Dent. Bone is a strong, flexible and semi-rigid supporting tissue. eCollection 2020. doi: 10.1016/j.matbio.2016.02.001, Saito, M., Marumo, K. (2015). (2019). Healthc. With the same regulation mechanism as MGP, type I collagen can also act as an inhibitor of bone development by osteoclasts. doi: 10.1590/1678-7757-2016-0531, Finkelman, R. D., Butler, W. T. (1985). Thus, the implant can be designed for improved bionic mechanical properties and stronger bone regeneration ability. 2016, 6397820. doi: 10.1155/2016/6397820, Hu, W. S. (1992). Osteopontin is a negative regulator of proliferation and differentiation in MC3T3-E1 pre-osteoblastic cells. 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. Part A 18, 295–309. In addition, Haj et al. Extracellular matrix proteoglycans control the fate of bone marrow stromal cells. 26, e20160531. However, TSP2 promotes osteoblast mineralization by promoting the organization of osteoblast-derived ECM (Alford et al., 2010). (2005). 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. J. Mol. Moreover, its exact composition differs based on sex, age, and health conditions. Appearance of dentin gamma-carboxyglutamic acid-containing proteins in developing rat molars in vitro. Osteoblast-lineage cells are bone-forming cells in bone remodeling. Biotechnol. 7, 1700660. doi: 10.1002/adhm.201700660, Lin, X., Xiao, Y., Chen, Z., Ma, J., Qiu, W., Zhang, K., et al. Biphasic organo-bioceramic fibrous composite as a biomimetic extracellular matrix for bone tissue regeneration. It can withstand compression forces, and yet it can bend. BMSCs are capable of migration, proliferation, differentiation, and cell-cell communication. Med. J. R. Soc. Interestingly, the osteogenic potential of hydroxyapatite/β‐tricalcium phosphate (HA/β‐TCP) was improved by surface immobilization of MEPE peptide. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. 2020 Dec 7;9(12):2630. doi: 10.3390/cells9122630. doi: 10.1111/cpr.12658, Lin, X., Zhao, C., Zhu, P., Chen, J., Yu, H., Cai, Y., et al. Structurally, periostin comprises four domains, a signal sequence, a cysteine-rich emilin-like (EMI) domain, four repetitive and conserved FAS-1 domains, and a variable hydrophilic C-terminal domain, each of which provides different functions, such as FAS-1 providing cell adhesion ability (Merle and Garnero, 2012). Osteoinduction of bone grafting materials for bone repair and regeneration. By contrast, bone tissue formed only at the edge of the scaffold without dECM (Kim et al., 2018). J. Nanosci. The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. Med. Extracellular matrix dynamics during mesenchymal stem cells differentiation. 28, 183–194. Nevertheless, the clinical application of ECM-modified biomaterial scaffold or decellularized ECM scaffold in bone repair still faces many problems, such as the preservation of growth factors and biochemical signals in the ECM during decellularization, modification of the ECM, design, and processing of ECM scaffolds, and standardization and mass production for clinical studies. Decellularized extracellular matrix (dECM) has been established as a biomaterial that preserves a tissue's native environment, promotes cell proliferation, and provides cues for cell 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. The implantation of osteogenic ECM sheets (OECMS) that retain the native collagen I and growth factors, together with HA, enhanced bone regeneration in a rat model of femoral non-union at 5 and 8 weeks. doi: 10.1016/j.ydbio.2018.03.002, Bailey Dubose, K., Zayzafoon, M., Murphy-Ullrich, J. E. (2012). Sci. ECM scaffolds have unique advantages in all these areas. doi: 10.1016/j.bone.2015.05.046, Keywords: ECM, bone formation, bone tissue engineering, bone repair, bone cells, Citation: Lin X, Patil S, Gao Y-G and Qian A (2020) The Bone Extracellular Matrix in Bone Formation and Regeneration. (2016). J. doi: 10.1128/MCB.00012-19, Zoch, M. L., Clemens, T. L., Riddle, R. C. (2016). This is caused by increased inducible nitric oxide synthase (iNOS) (Amend et al., 2015). The formation of osteoclasts can be suppressed by full length or 30–75 kDa fragments of type I collagen, which binds with the collagen receptor LAIR-1 and thereby maintaining bone strength (Boraschi-Diaz et al., 2018). Cell Biol. Z., Cathey, A. L., Reddy, A. While additives can enhance the bone regeneration ability of the defect site, they must not affect the growth of other adjacent tissues at the graft site, hence avoiding inflammation and hyperplasia. Synergistic effect of extracellularly supplemented osteopontin and osteocalcin on stem cell proliferation, osteogenic differentiation, and angiogenic properties. 18, 807–817. It is composed predominantly of collagens, non-collagenous glycoproteins, hyaluronan and proteoglycans. Beyond that, dECM scaffolds for bone repair can also be obtained from other, non-bone cells. Decellularized Adipose Tissue Hydrogel Promotes Bone Regeneration in Critical-Sized Mouse Femoral Defect Model. 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). Cell Commun. doi: 10.1002/jbm.b.32648, Alford, A. I., Terkhorn, S. P., Reddy, A. doi: 10.2147/IJN.S124671, Onishi, T., Shimizu, T., Akahane, M., Omokawa, S., Okuda, A., Kira, T., et al. Biomaterials 34, 4404–4417. doi: 10.1016/j.jmbbm.2013.06.013, Noori, A., Ashrafi, S. J., Vaez-Ghaemi, R., Hatamian-Zaremi, A., Webster, T. J. Loss of bone sialoprotein leads to impaired endochondral bone development and mineralization. Most tissue engineering approaches rely on renewable seed cells, such as stem cells, to restore damaged sites. Nanotechnol. The extracellular matrix (ECM) is an intricate dynamic bio-environment with precisely regulated mechanical and biochemical properties. Front. demonstrated that a combination of decellularized adipose tissue (DAT) with adipose-derived stromal/stem cells (ASCs) is effective in the regenerative bone repair of mice critical-size femur defects. (2019). Oral. Whereby the efficiency of attachment between hMSCs and the PCL/HA scaffold was improved with a higher HA content of 5% to 10% and in a HA concentration-dependent manner (Kumar et al., 2017). (2015). Signal 3, 227–238. (2019). Front Bioeng Biotechnol. Drucker A, Yoo BH, Khan IA, Choi D, Montermini L, Liu X, Jovanovic S, Younis T, Rosen KV. (2017). Bone Regeneration With Osteogenically Enhanced Mesenchymal Stem Cells and Their Extracellular Matrix Proteins. Among the organic components, type I collagen provides the tensile strength … (2014). Moreover, periostin can also affect osteoblast differentiation and bone formation, suggesting that periostin is involved in bone anabolism by regulating Wnt/β‐catenin signaling (Merle and Garnero, 2012) (Table 3). Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine. The patients showed bony healing and new bone formation in the defect site (Govender et al., 2002; Calori et al., 2008). SLRPs are secreted extracellular proteins that interact with cell surface receptors and cytokines to regulate both normal and pathological cellular behaviors. doi: 10.22203/eCM.v036a06, Paiva, K. B. S., Granjeiro, J. M. (2017). Biol. doi: 10.1016/j.bone.2003.11.027, Igwe, J. C., Gao, Q., Kizivat, T., Kao, W. W., Kalajzic, I. Visualizing mRNA expression in plant protoplasts: factors influencing efficient mRNA uptake and translation. doi: 10.1007/s00264-011-1391-7, Holm, E., Aubin, J. E., Hunter, G. K., Beier, F., Goldberg, H. A. Cancer 8, 212–226. Matrix Gla protein inhibition of tooth mineralization. 206, 204–215. Hydroxyapatite-polymer biocomposites for bone regeneration: A review of current trends. Int 2014, 217078. doi: 10.1155/2014/217078, Roseti, L., Parisi, V., Petretta, M., Cavallo, C., Desando, G., Bartolotti, I., et al. Moreover, the GHA-MFE fiber scaffolds significantly increased the rate of new bone formation in rabbit femoral cortical bone defect after 4 weeks of implantation compared with commercial Surgiwear™ (Shamaz et al., 2015). Obviously, the surface morphology and overall topology of ECM in scaffolds are significantly involved in determining their capacity for cell loading and growth in bone tissue engineering. Along with soluble RANKL, macrophage-colony stimulating factor (M-CSF) binds to the colony-stimulating factor-1 (C-FMS) receptor on osteoclast progenitors to initiate osteoclast differentiation. J. Clin. doi: 10.1016/j.bone.2014.10.007, Hoshiba, T., Chen, G. P., Endo, C., Maruyama, H., Wakui, M., Nemoto, E., et al. Circulating OCN not only acts as a hormone that regulates glucose and energy metabolism, but its concentration in serum can be used as a biochemical indicator of bone formation (Mizokami et al., 2017). Cell-Derived Extracellular Matrix: Basic Characteristics and Current Applications in Orthopedic Tissue Engineering. Once osteoclastogenesis is initiated, mono-nucleate osteoclast precursors fuse together to form multi-nucleate, mature osteoclasts. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. doi: 10.1016/j.bone.2009.08.058, PubMed Abstract | CrossRef Full Text | Google Scholar, Alford, A. I., Golicz, A.  |  (2009). doi: 10.2174/138161209787846739. The Col-Ap nanocomposite scaffold was able to activate bone-forming cells, promote inward vascularization, as well as induce the synthesis of the ECM mediated by increased TGFβ1. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. The main inorganic constituent of hard tissues, such as bone and dentine, is hydroxyapatite (HA, Ca5(PO4)3OH) (Ramesh et al., 2018). J. 87, 839–844. Deciphering the Relevance of Bone ECM Signaling. Cytotechnology 10, 187–188. 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. Thrombospondin-2 and SPARC/osteonectin are critical regulators of bone remodeling. Bone contains 100s of extracellular matrix (ECM) proteins and the ECM of the various bone tissue compartments plays essential roles directing the remodeling of bone through the coupled … (2017). The most abundant mineral is calcium phosphate, although magnesium, carbonate, and fluoride ions are also present. As the physical basis of artificial grafts, scaffold materials play a key role in the construction of artificial bone (Noori et al., 2017). Osteogenic Extracellular Matrix Sheet for Bone Tissue Regeneration. However, many such novel materials suffer from shortcomings such as poor biocompatibility, low osteoinductivity, and high immunogenicity. A., Mazharian, A., Komarova, S. V. (2018). 20, 942. doi: 10.3390/ijms20040942, Xie, J., Peng, C., Zhao, Q. H., Wang, X. L., Yuan, H. H., Yang, L. L., et al. Tissue Eng. J. J. (2015). Growth plate extracellular matrix-derived scaffolds for large bone defect healing. doi: 10.1016/j.bbrc.2012.05.020, Bellahcene, A., Castronovo, V., Ogbureke, K. U., Fisher, L. W., Fedarko, N. S. (2008). 97, 463–470. J. Biomater. These are considered to be important for MSC homing and fate determination, such as adhesion, expansion, and spreading, through integrin receptors. The ideal scaffold should also promote the attachment, increase the viability and proliferation, as well as induce osteogenic differentiation and angiogenesis. -. Cell Bio 15, 786–801. (2019). C-Mater. In vitro, adipose‐derived stem cells (ASCs) on hMSCs derived decellularized ECM showed more osteogenic colonies, accompanied by increased expression of osteogenic markers (Zhang et al., 2015). Integrin-matrix combination is vital for podosome formation on osteoclasts. Further development of 3D printing technology in ECM-based scaffolds is beneficial to the field of bone tissue engineering and regenerative medicine. 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). BSP can promote bone resorption, and the migration of preosteoclast and mature osteoclasts is impaired in the absence of BSP (Boudiffa et al., 2010). Ideal scaffolds must have good biocompatibility, biodegradability, biomechanical properties, permeability, surface characteristics, and must not promote immune rejection (Yi et al., 2017). Osteopenia and decreased bone formation in osteonectin-deficient mice. doi: 10.1016/j.bbrc.2018.05.092, Zhang, J., Ma, Z., Yan, K., Wang, Y., Yang, Y., Wu, X. Isolation, production, and analysis of small leucine-rich proteoglycans in bone. (2015). On account of the synergistic effect of stem cells and ECM, the stem cells/ECM composite scaffolds are more conducive to bone remodeling than ECM modified scaffolds. NIH 51, 1013–1026. Res. Am. On the other hand, OCN promotes the differentiation of MSCs into osteoblasts, with the increase of extracellular calcium levels, ALP activity, and the mRNA expression of OPN and OCN (Carvalho et al., 2019a). Mesenchymal stromal cells derived from human nasal inferior turbinate tissue (hTMSCs) were combined with a 3D-printed PCL/poly(lactic-co-glycolic acid) (PLGA)/β-TCP scaffold to form a mineralized ECM scaffold. ECM scaffolds derived from stem cells and bone cells can potentially better mimic the native bone microenvironment, thereby inducing bone regeneration (Sun et al., 2018). Like BSP, OPN is a major regulator of bone formation, mineralization, especially in bone turnover. 2015;65:20–31. Further studies are still needed to fully reveal the multiple functions of ECM in the ECM-modified biomaterial scaffold during bone repair. J. Dent. (2016). RANKL and M-CSF are the two key factors in osteoclast differentiation and formation. 30, 106–115. No use, distribution or reproduction is permitted which does not comply with these terms. doi: 10.1016/j.biocel.2015.05.008. (2019). Dev. Pharmacol. (2016). 2. 54, 275–282. Among the organic components, type I collagen provides the tensile strength of bone. constructed polycaprolactone-co-lactide (PCL) scaffolds coated with 3D collagen I/chondroitin sulfate (Coll I/CS) to repair rabbit calvarial bone defects. Cytoskeletal control of nuclear morphology and stiffness are required for OPN-induced bone-marrow-derived mesenchymal stem cell migration. 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). Mice lacking DMP1 show severe bone defects, displaying increased serum fibroblast growth factor 23 (FGF23) and decreased serum phosphorus, as well as deformed and low-mineralized bone (Jani et al., 2016). 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). (2018). Newly formed bones undergo physiological remodeling mediated by osteoclasts (Acharya et al., 2012). Histochem. Knockdown of MGP inhibits the differentiation and mineralization of osteoblasts via up-regulating Wnt/β-catenin signaling pathway. Adverse reactions and events related to musculoskeletal allografts: reviewed by the World Health Organisation Project NOTIFY. eCollection 2020. (2018). Therefore, the dynamic assembly of bone collagen contributes greatly to the encapsulation and mineralization of osteocytes in bone matrix (Shiflett et al., 2019). Taken together, ECM that participates in bone formation and mineralization also significantly contributes to the growth, survival, and differentiation of MSCs (Table 2). Gross anatomy of the long bones. 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). Moreover, it remains unknown how much each of these factors or the combination of these factors contributes to ECM in the scaffold. D'Angelo E, Lindoso RS, Sensi F, Pucciarelli S, Bussolati B, Agostini M, Collino F. Front Oncol. DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease. As a wnt agonist, R-spondin2 is abundantly expressed in pre-osteoblasts stimulated by Wnt. However, under pathological conditions, including osteoporosis and cancer, bone remodeling is dysregulated. In some cases, it is actually secreted by the surrounding cells. It can promote osteoblast differentiation and enhance early bone mineralization to produce new bone in vivo. This image shows cellular comparisons between 2D and 3D hydrogels. The extracellular matrix of bone tissue is largely composed of collagen and inorganic salts. Int. doi: 10.1002/jbmr.2320, Coulson-Thomas, Y. M., Coulson-Thomas, V. J., Norton, A. L., Gesteira, T. F., Cavalheiro, R. P., Meneghetti, M. C., et al. R-spondin-2 is a Wnt agonist that regulates osteoblast activity and bone mass. TSP1 inhibits the mineralization of osteoblast in vitro and in vivo (Ueno et al., 2006). Tissue engineering strategies that utilize the functional ECM are superior at guiding the formation of specific tissues at the implantation site. Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis. Type III collagen regulates osteoblastogenesis and the quantity of trabecular bone. Z., Xu, G. W., et al. Regener. doi: 10.1089/ten.teb.2015.0290, Zhang, D. M., Zhou, C. C., Wang, Q. X., Cai, L. Y., Du, W., Li, X. This means that native decellularized bone transplantation has a broad application prospect in orthopedic surgery. SLRP and thrombospondins can regulate collagen assembly by interacting with collagen fibrils. Decellularized Extracellular Matrix as an In Vitro Model to Study the Comprehensive Roles of the ECM in Stem Cell Differentiation. J. BioMed. Mater. The potential … Osteoblasts derived…, Mature, multi-nucleated osteoclast in vitro.…, Mature, multi-nucleated osteoclast in vitro. 78, 1246–1262. 73 The bone ECM is unique in that it is highly mineralized (comprising 50‐70% of its total … The HA/β‐TCP with the MEPE peptide stimulated bone regeneration in a mouse calvarial defect model compared to unmodified HA/β‐TCP. (2018). 18, 564. doi: 10.3390/ijms18030564, Shiflett, L. A., Tiede-Lewis, L. M., Xie, Y., Lu, Y., Ray, E. C., Dallas, S. L. (2019). Osteocytes are terminally differentiated osteoblasts that have become embedded in the bone matrix. OPN and BSP can act as a network to coordinate the function of osteoclasts. Periosteum Extracellular-Matrix-Mediated Acellular Mineralization during Bone Formation. This might due to increased secretion of Alp and Col (Xie et al., 2016). doi: 10.1016/j.matbio.2015.12.001, Kaipatur, N. R., Murshed, M., McKee, M. D. (2008). Table 3 Function of the bone ECM in osteoblasts. Transl. doi: 10.1016/j.bone.2018.12.001, Calori, G. M., Tagliabue, L., Gala, L., d'Imporzano, M., Peretti, G., Albisetti, W. (2008). It is occupied by a kind of aqueous gel of polysaccharides and fibrous proteins, together with other molecules dispersed in it, such as electrolytes, enzymes and chemical transmitters. The osteoclast has multiple nuclei (blue arrows) and stained tartrate resistant acid phosphatase (TRAP) positive, indicative of a mature osteoclast. Stem Cell Res. 39, e00012–19. Mol. Rickets also causes poor calcification of the cartilage extracellular matrix, impairing the ability to grow long bones. TNFα has been shown to regulate osteoclast differentiation and survival in a RANKL-independent manner. Bone and bone mineral matrix are produced by osteoblasts and regulated by osteoclasts, which break down bone. 97, 229–240. ECM is not … New insights into the biology of osteocalcin. Nanoparticles for bone tissue engineering. Cell Endocrinol. Co 501, 968–973. (2018). After 6 months, active bone formation can be detected in both callus and graft of the patient (Hesse et al., 2010).  |  Obviously, MGP is responsible for disrupting bone formation and inhibiting mineralization. 2011;3:a005058. Mol. These fibrils interact with other collagenous and noncollagenous proteins to assemble the higher-order fibril bundles and fibers (Varma et al., 2016). 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. (2002). (A) ECM-modified biomaterials scaffold. Vitamin K-dependent proteins involved in bone and cardiovascular health. 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). Biglycan and decorin are class I SLRPs that contain either dermatan or chondroitin sulfate GAG chains. (2011). However, due to the complex anatomical structure of bone and the high mechanical stress that the engineered tissue must withstand in vivo, bone tissue regeneration remains one of the major challenges of tissue engineering (Vieira et al., 2017). 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). Bone Res. Tissue Int. Bioph. The bone matrix is manipulated to promote cancer growth. MEPE expression in osteocytes during orthodontic tooth movement. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM. A. Type I collagen fibrils in bone ECM also modulate osteogenesis by binding with integrins of osteoblast progenitors, which leads to initiated osteoblast differentiation cascade through Runx2 transcriptional activation (Elango et al., 2019). When a dECM derived from MG63 cells was deposited on a CS/PCL scaffold, hMSCs exhibited enhanced attachment, proliferation, and osteogenic differentiation, and the scaffold showed anti-inflammatory features in vitro. doi: 10.1016/j.bpj.2016.05.038, Vieira, S., Vial, S., Reis, R. L., Oliveira, J. M. (2017). 19, 18. doi: 10.1186/s40510-018-0216-2, Sun, T., Yao, S., Liu, M., Yang, Y., Ji, Y., Cui, W., et al. The main function of collagens is mechanical support and to act as a scaffold for bone cells (Saito and Marumo, 2015). Share it! MEPE knockout mice show increased bone mass, accompanied by suppressed mineralization, suggesting that both DMP1 and MEPE can regulate the mineralization in osteocytes and lacunar wall (Gluhak-Heinrich et al., 2007) (Table 4). 36, 69–80. 422, 488–493. The organization of the osteocyte network mirrors the extracellular matrix orientation in bone. doi: 10.1016/j.mce.2015.12.014, Boraschi-Diaz, I., Mort, J. S., Bromme, D., Senis, Y. Collagen type I coating stimulates bone regeneration and osteointegration of titanium implants in the osteopenic rat. 432, 75–82. J. Mol. Keywords:Extracellular matrix, cartilage, bone, collagen, proteoglycan, growth factor Abstract: The extracellular matrix … Finally, the ECM can be modified by adding growth factors and bioactive molecules during the preparation of ECM scaffolds to improve the effectiveness of bone defect repair. B. Res. Bone ECM dynamically interacts with osteoblast-lineage cells and osteoclasts to regulate the formation of new bone during regeneration. This scaffold promoted the viability, proliferation, and osteogenesis of rat MSCs through the ERK1/2 and Smad1/5/8 signal pathways in vitro. Exogenous biglycan or fibromodulin weakens the ability of osteoclast precursors to form TRAP-positive multinucleated cells. The dECM/PLGA/PLA scaffold significantly promoted new bone formation in a rat model of a calvarial bone defect. doi: 10.3892/mmr.2018.8940, Wu, Y. With the rapid development of bone regenerative medicine, the osteoinductive, osteoconductive, and osteogenic potential of ECM-based scaffolds has attracted increasing attention. Different structures composed of type I collagen have different effects on the behavior of osteoblasts. Stem Cells Int. In addition, 3D ECM scaffold produced from decellularized periosteum promoted bone mineralization by controlling the size and direction of mineral crystals in rabbit bone defect regeneration, suggesting the crucial role of periosteum ECM in efficient healing of fractures and bone regeneration (Lin et al., 2018). Therefore, ECs in OMSC/EC‐scaffold plays an important role in bone formation and vascularization (Li et al., 2019). Interface 13, 20160462. doi: 10.1098/rsif.2016.0462, Tsai, S. W., Cheng, Y. H., Chang, Y., Liu, H. L., Tsai, W. B. Int. Bone grafts can be used to stimulate or increase the formation of new bone around fractures or surgical implants, as well as to regenerate or replace the bone lost due to infection, trauma, or disease (Polo-Corrales et al., 2014). Moreover, eggshell-derived nano-hydroxyapatite for bone transplantation has strong safety and can obtain good bone regeneration performance. doi: 10.1002/jcp.20735, Varma, S., Orgel, J. P. R. O., Schieber, J. D. (2016). Kim et al. J. Struct. The bone marrow is located in the diaphysis, or shaft of long bones. Secreted RANKL can bind to the receptor activator of nuclear-factor kappa-β (RANK) receptor on osteoclast progenitor cells and initiate differentiation of osteoclast precursors. Connect Tissue Res. Rev. Matrix Biol. Bone ECM has been demonstrated to enhance bone regeneration. The identification of proteoglycans and glycosaminoglycans in archaeological human bones and teeth. 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. Copyright © 2020 Lin, Patil, Gao and Qian. The OECMS contained TGF-β and BMP2, leading to increased osteoinduction and osteoconduction (Onishi et al., 2018).