Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation.
The characteristic cupping of the optic nerve head (ONH) in glaucoma is associated with elevated TGF-beta2 and increased synthesis and deposition of extracellular matrix (ECM) proteins. In addition to TGF-beta2, the human ONH also expresses bone morphogenetic proteins (BMPs) and BMP receptors, which are members of the TGF-beta superfamily. We examined the potential effects of BMP4 and the BMP antagonist gremlin on TGF-beta2 induction of ECM proteins in ONH cells. BMP-4 dose dependently inhibited TGF-beta2-induced fibronectin (FN) and PAI-1 expression in ONH astrocytes and lamina cribrosa (LC) cells and also reduced TGF-beta2 stimulation of collagen I, collagen VI, and elastin. Addition of gremlin blocked this BMP-4 response, increasing cellular and secreted FN as well as PAI-1 levels in both cell types. Gremlin was expressed in ONH tissues and ONH cells, and gremlin protein levels were significantly increased in the LC region of human glaucomatous ONH tissues. Interestingly, recombinant gremlin dose dependently increased ECM protein expression in cultured ONH astrocytes and LC cells. Gremlin stimulation of ECM required activation of TGF-beta receptor and R-Smad3. TGF-beta2 increased gremlin mRNA expression and protein levels in ONH cells. Inhibition of either the type I TGF-beta receptor or Smad3 phosphorylation blocked TGF-beta2-induced gremlin expression. In conclusion, BMP4 blocked the TGF-beta2 induction of ECM proteins in ONH cells. The BMP antagonist gremlin reversed this inhibition, allowing TGF-beta2 stimulation of ECM synthesis. Increased expression of gremlin in the glaucomatous ONH may further exacerbate TGF-beta2 effects on ONH ECM metabolism by inhibiting BMP-4 antagonism of TGF-beta2 signaling. Modulation of the ECM via gremlin provides a novel therapeutic target for glaucoma.
Zode
Gulab S
GS
Department of Cell Biology and Genetics, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107, USA.
Clark
Abbot F
AF
Wordinger
Robert J
RJ
D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D005901:Glaucoma / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009898:Optic Disk / Q000378:metabolism*; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C051321:SERPINE1 protein, human; D051900:Smad3 Protein; D053781:Transforming Growth Factor beta2; D003094:Collagen; D004549:Elastin