Table 3.

GAGs and PGs: their role in physiology and pathologic processes [19]

	Type and presence	Physiology	Pathology
C4S (CS-A)	Sulfated galactosaminoglycan; cartilage, skin and tendon	Binds Ca2+, Cu2+ and Fe2+ ions; antioxidant (better then C6S and HA)	Decreased in OA, mediate adherence of plasmodium infected red blood cells
C6S (CS-C)	Sulfated galactosaminoglycan; cartilage, brain secretory granules	Reduces proinflammatory cytokines, MMPs, NO, and apoptosis	Laryngeal cancer, decreased in OA, increased in early atherosclerotic lesions
DS (CS-B)	Sulfated galactosaminoglycan; skin, blood vessels, heart, tendons, lungs	Regulation ECM integrity and cellular signaling; DS selectively activates heparin cofactor II that inactivates thrombin; carcinogenesis, wound repair, and fibrosis; DS binds water, coagulation	Dermatan sulfate accumulates abnormally in several of the mucopolysaccharidosis disorders and in myxomatous degeneration. Involved in cardiovascular disease, infection, fibrosis
HA	Lack sulfation and epimerization of glucuronic acid moiety to uronic acid, the only GAG synthesized in the cytoplasm at the plasma membrane and also the only GAG that is synthesized without core protein. Connective, epithelial and neural tissue. abundant in cartilage and bone	Early development, tissue organization, cell proliferation, facilitate migration and condensation of mesenchymal cells, participates in joint cavity formation, binds and immobilizes aggrecan, regulates osteoblast and osteoclast function. HA works as a scaffold for building PGs, suppresses cartilage degeneration and reduce pain perception, associated with cell adhesion and motility, suppresses prostaglandin E2 and IL-1 production, activates SRC, FAK, ERK and PKC whereas interaction with CD44 also regulates ERBB, PI3K, regulates phosphorylation of BAD and hence promotes cell survival, contributes to cell proliferation and migration, bone turnover, involved in tissue repair in skin, binds to receptor CD44	Used for treatment of osteoarthritis
HS	Sulfated glucosaminoglycan; all types of cells, highly abundant in ECM of the skeleton	Coreceptors for morphogens, sequester growth factors and cytokines to regulate cell differentiation and growth, compose ECM scaffolds that make physical separation of the niche from cellular and signaling influence of surrounding environment, involved in skeletal patterning, differentiation, growth and homeostasis, critical for hematopoietic stem cell inch, Ndst1 mutation causes brain/skull defects and lung surfactant problems resulting in perinatal lethality, Ndst2 mutant have defective granule formation in mast cells, stimulates angiogenesis, osteocastogenesis, skeletal patterning, differentiation and homeostasis, coreceptor for morphogens, sequester growth factors and cytokines to regulate cell differentiation and growth, FGF-binding, binds fibronectin	Sequesters chemokines or FGF towards migrating tumor cells, promotes metastasis, multiple osteochondromas (MO)—benign bone cartilaginous tumor caused by mutant in EXT1 or EXT2, accumulated in mucopolysaccharidoses
KS	Sulfated glucosaminoglycan; N-glycan KSI or O-glycan KSII. Highly abundant in cornea and cartilage. Also found in epithelial tissue, central nervous system	Maintains proper special organization of the type I collagen fibrils and promotes transparency of cornea, cellular recognition of protein ligands, cell motility	Corneal opacity and corneal dystrophy (KS lacks GlcNAc sulfation), epithelial-derived carcinoma cells, alerted sulfation levels of KS was found in brain of Alzheimer patients
Aggrecan	O- and N-linked KSII, CS, DS, KS (HS absent), cartilage	Maintains tissue hydration, contributes to the mechanical properties of tissue, inhibits migration of neural crest cells, null mice show cartilage defects and delay in bone development	Chondrodystrophy, nanomelia, cartilage matrix deficiency (CMD), murine brachymorphism (bm), spondyloepimetaphyseal dysplasia enhanced expression in chondroblastoma, chondroma, chondrosarcoma, osteosarcoma, decreased in squamous cell carcinoma chondrodystrophy, nanomelia, cartilage matrix deficiency, spondyloepimataphyseal dysplasia
Biglycan	CS, DS (HS absent), bone, cartilage, skin, connective tissue	Activates cell division, organization of collage fibers, increased in vascular injury, upregulates p27 and downregulates cyclin A and proliferating cell nuclear antigen, maintaining proper number of mature osteoblasts and survival of bone marrow stromal cells, organization of collagen fibers, regulator of cell cycle, binds TGF-beta	Overexpressed in pancreatic cancer and hyperplasic thymus osteoporosis
Decorin	CS, DS (HS absent), connective tissue, cornea	Inhibits collagen fiber formation by interaction with col I, col II, and col VI, inhibits cell division, adhesion, increased in vascular injury, downregulates Erbb2 and MAP kinases, upregulates p21 CDK inhibitor leading to inhibition of cell proliferation and specific induction of apoptosis in transformed cells. maintaining proper number of mature osteoblasts and maintaining survival of bone marrow stromal cells, bind nonfibril collagens XII and XIV, regulates cell proliferation, binds TGF-beta, mediates EGF signaling by binding to EGFR	Antiproliferative properties in tumor growth, overexpressed in colorectal carcinoma, colon adenocarcinoma, melanoma, osteosarcoma, basal cell carcinoma, inhibits migration of MG-63 osteosarcoma cells, reduced decorin levels were found in lung adenocarcinoma, squamous carcinoma, breast carcinoma, hepatocellular carcinoma and ovarian tumors, may regulate tumor angiogenesis, overexpression is often associated with shift from DS to CS, osteoporosis
Lumican	KS, cornea	Upregulates p27 and downregulates cyclin A and proliferating cell nuclear antigen, regulates collagen fibril organization and circumferential growth, corneal transparency, and epithelial cell migration and tissue repair	Upregulated in pancreatic, colorectal and breast cancers, stroma of salivary pleiotropic adenoma, reduced expression is correlated with progression of breast carcinoma
Perlecan	HS, CS, cartilage, limb bud mesenchyme, articular cartilage, bone marrow stroma, all basal membranes, vasculature	Growth factor signaling, collagen fibrillogenesis, structural stability, vasculogenesis, endorepellin, antiangiogenic factor, chondrocyte proliferation and differentiation, collagen I and II fibrillogenesis, vasculogenesis, mediator of Shh signaling, Wnt signaling, TGF-beta signaling in the skeleton, regulates FGF2 signaling	Schwartz–Jampel syndrome, dyssegmental dysplasia Silverman–Handmaker type (DDSH), perlecan-null embryo chondroplasia, prostate tumor metastasis
Versican	C6S>C4S>DS (HS, KS absent), connective tissue, aorta, brain; fibroblasts. important for vascular biology	Lipid retention, modification and accumulation, hydration of ECM, cell proliferation, migration, embryo development, binds HA, CD44, and chemokines	Promotes tumor growth and spread, expressed in the stroma of nearly all human cancers (prostate, breast, lung, ovarian cancers and odontogenic tumors, melanoma, brain tumors, pharyngeal squamous cell carcinoma, keratinocyte tumors, atherosclerosis)