title: Interactive cytokine regulation of synoviocyte lubricant secretion.
abstract: Cytokine regulation of synovial fluid (SF) lubricants, hyaluronan (HA), and proteoglycan 4 (PRG4) is important in health, injury, and disease of synovial joints, and may also provide powerful regulation of lubricant secretion in bioreactors for articulating tissues. This study assessed lubricant secretion rates by human synoviocytes and the molecular weight (MW) of secreted lubricants in response to interleukin (IL)-1beta, IL-17, IL-32, transforming growth factor-beta 1 (TGF-beta1), and tumor necrosis factor-alpha (TNF-alpha), applied individually and in all combinations. Lubricant secretion rates were assessed using ELISA and binding assays, and lubricant MW was assessed using gel electrophoresis and Western blotting. HA secretion rates were increased approximately 40-fold by IL-1beta, and increased synergistically to approximately 80-fold by the combination of IL-1beta + TGF-beta1 or TNF-alpha + IL-17. PRG4 secretion rates were increased approximately 80-fold by TGF-beta1, and this effect was counterbalanced by IL-1beta and TNF-alpha. HA MW was predominantly <1 MDa for controls and individual cytokine stimulation, but was concentrated at >3 MDa after stimulation by IL-1beta + TGF-beta1 + TNF-alpha to resemble the distribution in human SF. PRG4 MW was unaffected by cytokines and similar to that in human SF. These results contribute to an understanding of the relationship between SF cytokine and lubricant content in health, injury, and disease, and provide approaches for using cytokines to modulate lubricant secretion rates and MW to help achieve desired lubricant composition of fluid in bioreactors.
authors.affiliation: Department of Bioengineering, University of California-San Diego , La Jolla, CA, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Blewis
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lao
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Schumacher
authors.forename: William D
authors.initials: WD
authors.lastname: Bugbee
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D019149:Bioreactors; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D054327:Lubricants / Q000737:chemistry / Q000378:metabolism; D008970:Molecular Weight; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D023822:Tissue Engineering; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099158:Proteoglycan 4
chemical_list: D016207:Cytokines; D006820:Hyaluronic Acid; D020381:Interleukin-17; D053583:Interleukin-1beta; D007378:Interleukins; D054327:Lubricants; D011509:Proteoglycans; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C496971:IL32 protein, human; C419197:PRG4 protein, human; D000099158:Proteoglycan 4