{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hyaluronidase‐3 (HYAL3) is emerging as a context‐dependent regulator of hyaluronan (HA) metabolism and extracellular matrix remodeling. In a cardiac injury model, interleukin‐10 treatment decreased HYAL3 expression by approximately 28% post–myocardial infarction, which reduced HA degradation and limited collagen deposition, thereby contributing to improved wound healing and scar formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In contrast, studies in HYAL3 knockout mice revealed no major abnormalities in constitutive HA breakdown, suggesting that HYAL3 is not essential for baseline HA catabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Complementary cell culture investigations indicate that while overexpressed HYAL3 in mouse cells does not exhibit strong intrinsic hyaluronidase activity, it can augment Hyal1 expression and thereby enhance acid‐active HA-hydrolytic activity, implying an indirect regulatory role in HA metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the reproductive context, HYAL3 is present in human and mouse sperm as two distinct isoforms localized on the plasma membrane of the head and midpiece. This acid-active enzyme contributes to efficient cumulus penetration and acrosomal exocytosis, with HYAL3 deficiency resulting in delayed cumulus penetration and impaired exocytosis, thereby affecting fertilization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, genetic association studies have implicated polymorphisms in the HYAL3 gene with primary open-angle glaucoma, suggesting that variations in HYAL3 may affect HA metabolism within ocular tissues"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while rare heterozygous mutations in HYAL3 have been observed in lung squamous cell carcinoma and are correlated with lymph node metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Further, during osteoblast mineralization in the MG63 cell line, HYAL3 expression was markedly increased (approximately 13-fold), correlating with decreased HA production and alteration of glycosaminoglycan synthesis, which suggests a role in bone extracellular matrix modulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In naked mole-rats, a species noted for its cancer resistance, HYAL3 is systematically overexpressed alongside other HA-regulatory genes (such as Tnfaip6), a profile that may underlie their unique HA metabolism and contribute to their protective phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies underscore the multifaceted roles of HYAL3—from modulating inflammation-induced tissue remodeling and influencing fertilization to its potential involvement in pathological conditions such as glaucoma and cancer—highlighting its importance as a modulator of HA dynamics in both physiological and disease states.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mira Jung, Yonggang Ma, Rugmani Padmanabhan Iyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Basic Res Cardiol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00395-017-0622-5"}], "href": "https://doi.org/10.1007/s00395-017-0622-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28439731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28439731"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Vasantha Atmuri, Dianna C Martin, Richard Hemming, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyaluronidase 3 (HYAL3) knockout mice do not display evidence of hyaluronan accumulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2008.07.006"}], "href": "https://doi.org/10.1016/j.matbio.2008.07.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18762256"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18762256"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Richard Hemming, Dianna C Martin, Elzbieta Slominski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mouse Hyal3 encodes a 45- to 56-kDa glycoprotein whose overexpression increases hyaluronidase 1 activity in cultured cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Glycobiology (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/glycob/cwn006"}], "href": "https://doi.org/10.1093/glycob/cwn006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18234732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18234732"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kristen L Reese, Rolands G Aravindan, Genevieve S Griffiths, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acidic hyaluronidase activity is present in mouse sperm and is reduced in the absence of SPAM1: evidence for a role for hyaluronidase 3 in mouse and human sperm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Reprod Dev (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mrd.21217"}], "href": "https://doi.org/10.1002/mrd.21217"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20586096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20586096"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kaustuv Basu, Abhijit Sen, Kunal Ray, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic association and gene-gene interaction of HAS2, HABP1 and HYAL3 implicate hyaluronan metabolic genes in glaucomatous neurodegeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Markers (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2012/390539"}], "href": "https://doi.org/10.1155/2012/390539"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22960332"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22960332"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rong-xin Zhang, Jin-hai Zhu, Jiang Fan, et al. 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