Retinoic acid and the transcription factor MafB act together and differentially to regulate aggrecan and matrix metalloproteinase gene expression in neonatal chondrocytes

Abstract

Vitamin A (VA) and its active form, retinoic acid (RA), are regulators of skeletal development and chondrogenesis. MafB, a transcription factor, has been identified as an important mediator in monocyte and osteoclast differentiation. However, the presence and function of MafB in chondrocytes is not clear. In this study, MafB gene expression was regulated by both the VA status of the mother (VA-marginal, adequate, and supplemented diets) and by direct oral supplementation of the neonates with VARA (VA mixed with 10% RA). Expression was highest in neonates of VA-supplemented versus VA-marginal dams (P<0.05), and in VARA-treated versus placebo-treated neonates across all diet groups (P<0.05). To examine cellular changes, primary chondrocytes derived from neonatal rat ribs were cultured in the presence of RA for up to 48 h. MafB mRNA exhibited a time- and dose-dependent increase in response to RA, while the induction of MafB mRNA was attenuated by BMS-493, a pan-RAR inverse agonist, implicating RAR signaling in the regulation of MafB. The genetic knockdown of MafB in chondrocytes using siRNA (MafBSI chondrocytes) abrogated the RA-induced increase in MafB expression. MafBSI chondrocytes expressed higher levels of aggrecan mRNA. Additionally, the increased matrix metalloproteinase (MMP)3 and MMP13 gene expression due to RA was attenuated in MafBSI chondrocytes, while total extracellular matrix staining was increased. These results support a role for MafB as a regulator of chondrocyte gene expression and matrix formation via control of aggrecan, MMP3 and MMP13 expression, and indicate an important role for RA in the regulation of MafB.

Influence of retinoic acid on human gingival epithelial barriers

“…Potential pan‐RARs were designed based on BMS 493 . In chondrocytes it was shown to block completely the RA‐induced increase in MafB expression . In the study of Zhang and Ross the RA was used in a concentration of 20 n m while the inhibitor was used in a concentration of 1 μ m .…”

MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis

“…MAFB is a transcription factor of the large MAF subfamily (MAFA, cMAF, MAFB, NRL) that binds to a specific DNA element (MARE); heterodimerizes with cMAF, JUN, and FOS (17)(18)(19); and associates and functionally inhibits MYB (19), MITF, and NFATc1 (20). MAFB controls lens development (21), lymphangiogenesis (22), pancreatic a and b cell differentiation (23,24), skin cell differentiation (25), chondrocyte matrix formation and development (26), and podocyte generation (27)(28)(29)(30), and also regulates type I IFN production through recruitment of coactivators to IFN regulatory factor 3 (31). Within the murine myeloid lineage, MafB is preferentially expressed in most tissue-resident macrophages, whose specific enhancers contain an overrepresentation of MARE sequences (32).…”

Inhibition of Elastase-Pulmonary Emphysema in Dominant-Negative MafB Transgenic Mice

“…Zhang et al reported that retinoic acid-induced MMP-3 and MMP-13 gene expression was attenuated in MafB-knockdown chondrocytes 36. MMP-3 and MMP-13 are induced in terminally differentiated chondrocytes, and MMP-12 is produced by differentiated macrophages 37.…”