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53-459: 15117 ENSG00000170961 ENSMUSG00000022367 Q92819 P70312 NM_005328 NM_008216 NP_005319 NP_032242 Hyaluronan synthase 2 is an enzyme that in humans is encoded by the HAS2 gene . Hyaluronan or hyaluronic acid is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of
106-435: A gene on human chromosome 8 is a stub . You can help Misplaced Pages by expanding it . Hyaluronan Hyaluronic acid ( / ˌ h aɪ . ə l j ʊəˈr ɒ n ɪ k / ; abbreviated HA ; conjugate base hyaluronate ), also called hyaluronan , is an anionic , nonsulfated glycosaminoglycan distributed widely throughout connective , epithelial , and neural tissues . It is unique among glycosaminoglycans as it
159-410: A bifunctional crosslinking agent 1,4-Butanediol diglycidyl ether (BDDE) using a ResonantAcoustic mixer over a period of time ranging from about 1 minute to about 10 minutes. Due to its ability to regulate angiogenesis by stimulating endothelial cells to proliferate in vitro, hyaluronan can be used to create hydrogels to study vascular morphogenesis. Cell proliferation Cell proliferation
212-469: A hydrogel. Crosslinking may allow a desired shape, as well as to deliver therapeutic molecules into a host. Hyaluronan can be crosslinked by attaching thiols (see thiomers ) (trade names: Extracel, HyStem), hexadecylamides (trade name: Hymovis), and tyramines (trade name: Corgel). Hyaluronan can also be crosslinked directly with formaldehyde (trade name: Hylan-A) or with divinylsulfone (trade name: Hylan-B). Hyaluronic acid can also be crosslinked with
265-469: A key role in tissue regeneration , inflammation response, and angiogenesis , which are phases of wound repair . As of 2023, however, reviews of its effect on healing for chronic wounds including burns , diabetic foot ulcers or surgical skin repairs show either insufficient evidence or only limited positive clinical research evidence. There is also some limited evidence to suggest that hyaluronic acid may be beneficial for ulcer healing and may help to
318-421: A matrix through which cells can migrate. Hyaluronic acid is produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts . Changes in the serum concentration of hyaluronic acid are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of hyaluronic acid with the leukocyte receptor CD44
371-433: A number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM . Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes . Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells. Although hyaluronan binds to receptor CD44, there
424-452: A population is determined by the rate of cell proliferation minus the rate of cell death . Cell size depends on both cell growth and cell division, with a disproportionate increase in the rate of cell growth leading to production of larger cells and a disproportionate increase in the rate of cell division leading to production of many smaller cells. Cell proliferation typically involves balanced cell growth and cell division rates that maintain
477-405: A role in virulence . Until the late 1970s, hyaluronic acid was described as a " goo " molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronic acid is a major component of the synovial fluid and was found to increase the viscosity of the fluid. Along with lubricin , it is one of the fluid's main lubricating components. Hyaluronic acid
530-408: A roughly constant cell size in the exponentially proliferating population of cells. Cell proliferation occurs by combining cell growth with regular "G1- S - M -G2" cell cycles to produce many diploid cell progeny. In single-celled organisms, cell proliferation is largely responsive to the availability of nutrients in the environment (or laboratory growth medium ). In multicellular organisms,
583-500: A small degree with pain control. Hyaluronic acid combines with water and swells to form a gel , making it useful in skin treatments as a dermal filler for facial wrinkles ; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US Food and Drug Administration . Granulation tissue is the perfused , fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from
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#1732787214246636-486: Is 3–4 million Da, and hyaluronic acid purified from human umbilical cord is 3,140,000 Da; other sources mention average molecular weight of 7 million Da for synovial fluid. Hyaluronic acid also contains silicon , ranging 350–1,900 μg/g depending on location in the organism. Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas
689-494: Is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery. It is typically injected using either a classic sharp hypodermic needle or a micro-cannula . Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections. Currently, hyaluronic acid is used as a soft tissue filler due to its bio-compatibility and possible reversibility using hyaluronidase . Complications include
742-535: Is a linear glycosaminoglycan (GAG), an anionic, gel-like, polymer, found in the extracellular matrix of epithelial and connective tissues of vertebrates. It is part of a family of structurally complex, linear, anionic polysaccharides. The carboxylate groups present in the molecule make it negatively charged, therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products. HA consists of repeating β4-glucuronic acid (GlcUA)-β3- N -acetylglucosamine (GlcNAc) disaccharides, and
795-474: Is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae . Fasciacytes are fibroblast-like cells found in fasciae. They are round-shaped with rounder nuclei and have less elongated cellular processes when compared with fibroblasts. Fasciacytes are clustered along the upper and lower surfaces of a fascial layer. Fasciacytes produce hyaluronan, which regulates fascial gliding. Hyaluronic acid (HA)
848-505: Is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive UVB rays , it becomes inflamed ( sunburn ), and the cells in the dermis stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure . While it is abundant in extracellular matrices , hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in
901-487: Is an important component of articular cartilage , where it is present as a coat around each cell ( chondrocyte ). When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but
954-508: Is crucial for the formation of granulation tissue; therefore, the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing. Cell migration is essential for the formation of granulation tissue. The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix. HA provides an open hydrated matrix that facilitates cell migration, whereas, in
1007-413: Is due to the strong solvation of these molecules. Hyaluronic acid is synthesized by a class of integral membrane proteins called hyaluronan synthases , of which vertebrates have three types: HAS1 , HAS2 , and HAS3 . These enzymes lengthen hyaluronan by repeatedly adding D -glucuronic acid and N -acetyl- D -glucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through
1060-421: Is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 ( TLR2 ), TLR4 , or both TLR2 and TLR4 in macrophages and dendritic cells . TLR and hyaluronan play a role in innate immunity . There are limitations including the in vivo loss of this compound limiting the duration of effect. As a major component of the extracellular matrix , hyaluronic acid has
1113-434: Is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but there is stimulation by high-molecular-weight hyaluronan (>500 kDa) when tested in cultured human synovial fibroblasts. Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product. A fasciacyte
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#17327872142461166-632: Is formed from hasC (UDP-glucose pyrophosphorylase) converting glucose-1-P into UDP-glucose, which then reacts with hasB (UDP-glucose dehydrogenase) to form UDP-glucuronic acid. The path forward from fructose-6-P utilizes glmS (amidotransferase) to form glucosamine-6-P. Then, glmM (Mutase) reacts with this product to form glucosamine-1-P. hasD (acetyltransferase) converts this into n-acetylglucosamine-1-P, and finally, hasD (pyrophosphorylase) converts this product into UDP-n-acetylglucosamine. UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase), completing
1219-543: Is fully metabolized in less than a week. According to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat . In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected. Due to its accumulation in airway epithelial cells in various respiratory diseases , such as COVID-19 , cystic fibrosis , influenza , and sepsis , hyaluronic acid
1272-422: Is important in tissue-specific homing by leukocytes, and overexpression of hyaluronic acid receptors has been correlated with tumor metastasis. HAS2 is a member of the vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to glycosaminoglycan synthetase (DG42) from Xenopus laevis , and human and murine hyaluronan synthase 1. This article on
1325-438: Is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. It is especially used for synovitis associated with equine osteoarthritis. It can be injected directly into an affected joint, or intravenously for less localized disorders. It may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. Intra-articularly administered medicine
1378-523: Is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus , and can be very large: human synovial HA averages about 7 MDa per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 MDa . Medically, hyaluronic acid is used to treat osteoarthritis of the knee, dry eye, for wound repair, and as a cosmetic filler. The average 70 kg (150 lb) person has roughly 15 grams of hyaluronan in
1431-513: Is produced on a large scale by extraction from animal tissues, such as chicken comb , and from Streptococci . Hyaluronic acid is a polymer of disaccharides , which are composed of D -glucuronic acid and N -acetyl- D -glucosamine , linked via alternating β-(1→4) and β-(1→3) glycosidic bonds . Hyaluronic acid can be 25,000 disaccharide repeats in length. Polymers of hyaluronic acid can range in size from 5,000 to 20,000,000 Da in vivo . The average molecular weight in human synovial fluid
1484-472: Is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy. By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration. Basically, HA is synthesized at the plasma membrane and released directly into
1537-519: Is synthesized by hyaluronan synthases (HAS), a class of integral membrane proteins that produce the well-defined, uniform chain lengths characteristic to HA. There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the HA polymer. For an HA capsule to be created, this enzyme must be present because it polymerizes UDP-sugar precursors into HA. HA precursors are synthesized by first phosphorylating glucose by hexokinase, yielding glucose-6-phosphate, which
1590-490: Is the main HA precursor. Then, two routes are taken to synthesize UDP-n-acetylglucosamine and UDP-glucuronic acid which both react to form HA. Glucose-6-phosphate gets converted to either fructose-6-phosphate with hasE (phosphoglucoisomerase), or glucose-1-phosphate using pgm (α-phosphoglucomutase), where those both undergo different sets of reactions. UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase). UDP-glucuronic acid
1643-485: Is the process by which a cell grows and divides to produce two daughter cells . Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth . Cell proliferation requires both cell growth and cell division to occur at the same time, such that the average size of cells remains constant in the population. Cell division can occur without cell growth, producing many progressively smaller cells (as in cleavage of
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1696-444: Is under study as a possible mediator of lung inflammatory mechanisms, as of 2022. The high biocompatibility of hyaluronic acid and its common presence in the extracellular matrix of tissues indicate its possible use as a biomaterial scaffold in tissue engineering . In particular, research groups have found hyaluronan's properties for tissue engineering and regenerative medicine may be improved with cross-linking, producing
1749-450: The extracellular matrix . It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds . Hyaluronic acid is synthesized by membrane-bound synthase at the inner surface of the plasma membrane , and the chains are extruded via ABC-Transporter into the extracellular space. It serves a variety of functions, including space filling, lubrication of joints, and provision of
1802-602: The HA-rich matrix pouches. Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. A report found HA content increases in the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and photoaging may be correlated, at least in part, with an increase of skin HA content, giving rise to increased tissue hydration. It has been suggested that
1855-470: The amount increases. A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of fibroblasts , embedded in dense fascial tissues, has been proposed as being cells specialized for the biosynthesis of the hyaluronan-rich matrix. Their related activity could be involved in regulating the sliding ability between adjacent muscular connective tissues. Hyaluronic acid
1908-412: The base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation, and organization of the granulation tissue matrix. Initiation of inflammation
1961-402: The body, one third of which is turned over (i.e., degraded and synthesized) per day. As one of the chief components of the extracellular matrix , it contributes significantly to cell proliferation and migration , and is involved in the progression of many malignant tumors . Hyaluronic acid is also a component of the group A streptococcal extracellular capsule , and is believed to play
2014-429: The cell membrane into the extracellular space. The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA. Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone ( hymecromone ), a 7-hydroxy-4-methylcoumarin derivative. This selective inhibition (without inhibiting other glycosaminoglycans ) may prove useful in preventing metastasis of malignant tumor cells. There
2067-411: The epidermis; its free-radical scavenging function, and its role in keratinocyte proliferation and migration. In normal skin, HA is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found. CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing
2120-452: The extracellular environment. This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment. HA plays an important role in the normal epidermis . HA also has crucial functions in the reepithelization process due to several of its properties. These include being an integral part of the extracellular matrix of basal keratinocytes , which are major constituents of
2173-407: The free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis. Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in
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2226-446: The late 1970s, intraocular lens implantation was often followed by severe corneal edema , due to endothelial cell damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed. The name "hyaluronan" is also used for a salt. Hyaluronan is used in treatment of articular disorders in horses , in particular those in competition or heavy work. It
2279-458: The latter scenario, directed migration and control of related cell mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated kinase , focal adhesion kinase , and other non-receptor tyrosine kinases . During fetal development, the migration path through which neural crest cells migrate
2332-405: The length of the chain and stabilise the molecule for its use in medical applications. The introduction of protein-based cross-links, the introduction of free-radical scavenging molecules such as sorbitol , and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid) are all techniques that have been used to preserve its shelf life. In
2385-471: The native high-molecular weight molecule, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant. Hyaluronan can also be degraded via non-enzymatic reactions. These include acidic and alkaline hydrolysis , ultrasonic disintegration , thermal decomposition , and degradation by oxidants . Hyaluronic acid is derived from hyalos (Greek for vitreous, meaning ‘glass-like’) and uronic acid because it
2438-542: The process of cell proliferation is tightly controlled by gene regulatory networks encoded in the genome and executed mainly by transcription factors including those regulated by signal transduction pathways elicited by growth factors during cell–cell communication in development . Recently it has been also demonstrated that cellular bicarbonate metabolism, which is responsible for cell proliferation, can be regulated by mTORC1 signaling. In addition, intake of nutrients in animals can induce circulating hormones of
2491-572: The severing of nerves and microvessels , pain, and bruising . Some side effects can also appear by way of erythema, itching, and vascular occlusion; vascular occlusion is the most worrisome side effect due to the possibility of skin necrosis, or even blindness in a patient. In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction . Hyaluronic acid is used to displace tissues away from tissues which are going to be subjected to radiation, for instance in one treatment option for some prostate cancers. Hyaluronic acid
2544-419: The smaller hydrogens assume the less-favorable axial positions. Hyaluronic acid in aqueous solutions self-associates to form transient clusters in solution. While it is considered a polyelectrolyte polymer chain, hyaluronic acid does not exhibit the polyelectrolyte peak, suggesting the absence of a characteristic length scale between the hyaluronic acid molecules and the emergence of a fractal clustering, which
2597-416: The synthesis. Hyaluronic acid can be degraded by a family of enzymes called hyaluronidases . In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors . The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro- angiogenic properties. In addition, recent studies showed hyaluronan fragments, not
2650-669: The wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes. Hyaluronic acid has been FDA-approved to treat osteoarthritis of the knee via intra-articular injection . A 2012 review showed that the quality of studies supporting this use was mostly poor, with a general absence of significant benefits, and that intra-articular injection of HA could possibly cause adverse effects . A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis. Hyaluronic acid has been used to treat dry eye . Hyaluronic acid
2703-561: The zygote ), while cell growth can occur without cell division to produce a single larger cell (as in growth of neurons ). Thus, cell proliferation is not synonymous with either cell growth or cell division, despite these terms sometimes being used interchangeably. Stem cells undergo cell proliferation to produce proliferating "transit amplifying" daughter cells that later differentiate to construct tissues during normal development and tissue growth, during tissue regeneration after damage , or in cancer . The total number of cells in
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#17327872142462756-439: Was developed in the 1970s and 1980s by Pharmacia , and approved for use in eye surgery (i.e., corneal transplantation , cataract surgery, glaucoma surgery, and surgery to repair retinal detachment ). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery. Native hyaluronic acid has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend
2809-449: Was first isolated from the vitreous humour and possesses a high uronic acid content. The term hyaluronate refers to the conjugate base of hyaluronic acid. Since the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan . Hyaluronic acid was first obtained by Karl Meyer and John Palmer in 1934 from the vitreous body in a cow's eye. The first hyaluronan biomedical product, Healon,
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