Editing Extracellular matrix (section)

== Structure ==
[[File:Extracellular Matrix.svg|thumb|1: Microfilaments 2: Phospholipid Bilayer 3: Integrin 4: Proteoglycan 5: Fibronectin 6: Collagen 7: Elastin]]
Components of the ECM are produced intracellularly by resident cells and secreted into the ECM via [[exocytosis]].<ref name=PG2007>{{cite book | vauthors = Plopper G | title = The extracellular matrix and cell adhesion, in Cells (eds Lewin B, Cassimeris L, Lingappa V, Plopper G) | location = Sudbury, MA | publisher = Jones and Bartlett | year = 2007 | isbn = 978-0-7637-3905-8 | url-access = registration | url = https://archive.org/details/cells0000unse }}</ref>  Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous [[protein]]s and [[glycosaminoglycan]]s (GAGs).{{cn|date=April 2025}}

===Proteoglycans===
[[Glycosaminoglycan]]s (GAGs) are [[carbohydrate]] [[polymer]]s and mostly attached to extracellular matrix proteins to form [[proteoglycan]]s (hyaluronic acid is a notable exception; see below). Proteoglycans have a net negative charge that attracts positively charged sodium ions (Na<sup>+</sup>), which attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store [[growth factors]] within the ECM.{{cn|date=April 2025}}

Described below are the different types of proteoglycan found within the extracellular matrix.{{cn|date=April 2025}}

====Heparan sulfate====
[[Heparan sulfate]] (HS) is a linear [[polysaccharide]] found in all animal tissues. It occurs as a [[proteoglycan]] (PG) in which two or three HS chains are attached in close proximity to cell surface or ECM proteins.<ref>{{cite book | title=Proteoglycans: structure, biology and molecular interactions | url=https://archive.org/details/proteoglycansstr00iozz | url-access=limited | vauthors = Gallagher JT, Lyon M | chapter=Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens | veditors = Iozzo RV | year=2000 | publisher=Marcel Dekker Inc. New York, New York | pages=[https://archive.org/details/proteoglycansstr00iozz/page/n41 27]–59 |isbn=9780824703349 }}</ref><ref>{{cite journal | vauthors = Iozzo RV | s2cid = 14638091 | title = Matrix proteoglycans: from molecular design to cellular function | journal = Annual Review of Biochemistry | volume = 67 | issue = 1 | pages = 609–52 | year = 1998 | pmid = 9759499 | doi = 10.1146/annurev.biochem.67.1.609 | doi-access = free }}{{closed access}}</ref>  It is in this form that HS binds to a variety of protein [[ligand]]s and regulates a wide variety of biological activities, including [[developmental processes]], [[angiogenesis]], [[blood coagulation]], and tumour [[metastasis]].{{cn|date=April 2025}}

In the extracellular matrix, especially [[basement membrane]]s, the [[protein domain|multi-domain]] proteins [[perlecan]], [[agrin]], and [[type XVIII collagen|collagen XVIII]] are the main proteins to which heparan sulfate is attached.{{cn|date=April 2025}}

====Chondroitin sulfate====
[[Chondroitin sulfate]]s contribute to the tensile strength of cartilage, [[tendon]]s, [[ligament]]s, and walls of the [[aorta]]. They have also been known to affect [[neuroplasticity]].<ref>{{cite book |doi=10.1016/S0070-2153(05)69008-4 |pmid=16243601 |chapter=Critical Period Mechanisms in Developing Visual Cortex |title=Neural Development |volume=69 |pages=215–237 |series=Current Topics in Developmental Biology |year=2005 |last1=Hensch |first1=Takao K. |isbn=978-0-12-153169-0 }}</ref>

====Keratan sulfate====
[[Keratan sulfate]]s have a variable sulfate content and, unlike many other GAGs, do not contain [[uronic acid]]. They are present in the [[cornea]], cartilage, [[bone]]s, and the [[Horn (anatomy)|horns]] of [[animal]]s.{{cn|date=April 2025}}

===Non-proteoglycan polysaccharide===
====Hyaluronic acid====
[[Hyaluronic acid]] (or "hyaluronan") is a [[polysaccharide]] consisting of alternating residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs, is not found as a proteoglycan. Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting [[turgor]] (swelling) force by absorbing significant amounts of water. Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief component of the interstitial gel. Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of the cell during biosynthesis.<ref name=MCB>{{cite book |vauthors=Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J | title = Molecular Cell Biology |year=2008 |url=https://archive.org/details/molecularcellbio00harv_624 |url-access=limited | edition = 5th | chapter = Integrating Cells Into Tissues | location = New York | publisher = WH Freeman and Company | pages = [https://archive.org/details/molecularcellbio00harv_624/page/n193 197]–234}}</ref>

Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, [[inflammation]], and [[tumor]] development. It interacts with a specific transmembrane receptor, [[CD44]].<ref>{{cite journal | vauthors = Peach RJ, Hollenbaugh D, Stamenkovic I, Aruffo A | title = Identification of hyaluronic acid binding sites in the extracellular domain of CD44 | journal = The Journal of Cell Biology | volume = 122 | issue = 1 | pages = 257–64 | date = July 1993 | pmid = 8314845 | pmc = 2119597 | doi = 10.1083/jcb.122.1.257 }}{{open access}}</ref>

===Proteins===
====Collagen====
[[Collagen]] is the most abundant protein in the ECM, and is the most abundant protein in the human body.<ref>{{cite journal | vauthors = Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD | title = Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen | journal = The Journal of Biological Chemistry | volume = 277 | issue = 6 | pages = 4223–31 | date = February 2002 | pmid = 11704682 | doi = 10.1074/jbc.M110709200 | doi-access = free }}{{open access}}</ref><ref>{{cite journal | vauthors = Karsenty G, Park RW | title = Regulation of type I collagen genes expression | journal = International Reviews of Immunology | volume = 12 | issue = 2–4 | pages = 177–85 | year = 1995 | pmid = 7650420 | doi = 10.3109/08830189509056711 }}{{closed access}}</ref> It accounts for 90% of bone matrix protein content.<ref>{{cite journal | vauthors = Kern B, Shen J, Starbuck M, Karsenty G | title = Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes | journal = The Journal of Biological Chemistry | volume = 276 | issue = 10 | pages = 7101–7 | date = March 2001 | pmid = 11106645 | doi = 10.1074/jbc.M006215200 | doi-access = free }}{{open access}}</ref> Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in [[Precursor (chemistry)|precursor]] form ([[procollagen]]), which is then cleaved by procollagen [[protease]]s to allow extracellular assembly. Disorders such as [[Ehlers Danlos Syndrome]], [[osteogenesis imperfecta]], and [[epidermolysis bullosa]] are linked with [[genetic defect]]s in collagen-encoding [[gene]]s.<ref name=PG2007/> The collagen can be divided into several families according to the types of structure they form:
# Fibrillar (Type I, II, III, V, XI)
# Facit (Type IX, XII, XIV)
# Short chain (Type VIII, X)
# Basement membrane (Type IV)
# Other (Type VI, VII, XIII)

====Elastin====
[[Elastin]]s, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. This is useful in [[blood vessels]], the [[lungs]], in [[skin]], and the [[ligamentum nuchae]], and these tissues contain high amounts of elastins. Elastins are synthesized by [[fibroblast]]s and [[smooth muscle]] cells. Elastins are highly insoluble, and [[tropoelastin]]s are secreted inside a [[chaperone molecule]], which releases the precursor molecule upon contact with a fiber of mature elastin. Tropoelastins are then deaminated to become incorporated into the elastin strand. Disorders such as [[cutis laxa]] and [[Williams syndrome]] are associated with deficient or absent elastin fibers in the ECM.<ref name=PG2007/>

===Extracellular vesicles===
In 2016, Huleihel et al., reported the presence of DNA, RNA, and Matrix-bound nanovesicles (MBVs) within ECM bioscaffolds.<ref name="Huleihel e1600502">{{cite journal | vauthors = Huleihel L, Hussey GS, Naranjo JD, Zhang L, Dziki JL, Turner NJ, Stolz DB, Badylak SF | title = Matrix-bound nanovesicles within ECM bioscaffolds | journal = Science Advances | volume = 2 | issue = 6 | pages = e1600502 | date = June 2016 | pmid = 27386584 | pmc = 4928894 | doi = 10.1126/sciadv.1600502 | bibcode = 2016SciA....2E0502H }}</ref> MBVs shape and size were found to be consistent with previously described [[Exosome (vesicle)|exosomes]]. MBVs cargo includes different protein molecules, lipids, DNA, fragments, and miRNAs. Similar to ECM bioscaffolds, MBVs can modify the activation state of macrophages and alter different cellular properties such as; proliferation, migration and cell cycle. MBVs are now believed to be an integral and functional key component of ECM bioscaffolds.{{cn|date=April 2025}}