Absence of transcription factor c-maf causes abnormal terminal differentiation of hypertrophic chondrocytes during endochondral bone development

Abstract

In this study, we report that the transcription factor c-Maf is required for normal chondrocyte differentiation during endochondral bone development. c-maf is expressed in hypertrophic chondrocytes during fetal development (E14.5-E18.5), with maximal expression in the tibia occurring at E15.5 and E16.5, in terminally differentiated chondrocytes. In c-maf-null mice, fetal bone length is decreased approximately 10%, and hypertrophic chondrocyte differentiation is perturbed. There is an initial decrease in the number of mature hypertrophic chondrocytes at E15.5 in c-maf-null tibiae, with decreased expression domains of collagen X and osteopontin, markers of hypertrophic and terminal hypertrophic chondrocytes, respectively. By E16.5, there is an expanded domain of late hypertrophic, osteopontin-positive chondrocytes in the c-maf-/-. This accumulation of hypertrophic chondrocytes persists and is still observed at 4 weeks of age. These data suggest that c-Maf facilitates the initial chondrocyte terminal differentiation and influences the disappearance of hypertrophic chondrocytes. BrdU and TUNEL analyses show normal proliferation rate and apoptosis in the c-maf-null. There is a specific decrease in MMP-13 expression at E15.5 in the c-maf-null. MMP-13 is known to be regulated by AP-1 and may also be a target of c-Maf. Thus, cartilage is a novel system in which c-Maf acts during development, where c-Maf is required for normal chondrocyte differentiation.

Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population

“…13 In addition, it can be transcriptionally upregulated in combination with SOX9 by the long form of the basic leucine zipper transcription factor, Lc-Maf, in chondrocytes, 14 which is an important factor in endochondral bone development and chondrocyte differentiation. 15 COL27A1 is developmentally regulated and is highly expressed in the developing cartilage and to a lesser extent in other tissues. 9,16 Protein expression of human COL27A1 accounts for B1.1% of all collagen transcripts in early human epiphyseal cartilage development.…”

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

“…In addition to T and NKT cells, c-Maf is expressed in a wide variety of rodent tissues and cell types, including the lens, kidney, brain, spleen, intestine, liver, cartilage, spinal cord dorsal horn, keratinocytes, developing hair germs, and cultured differentiating muscle cell lines [8][9][10][11][12][13]. This broad expression pattern suggests that c-Maf has functions apart from transactivation of the IL-4 gene.…”

“…A novel long form of c-Maf, Lc-Maf, regulates type II collagen via interactions with Sox9 [11]. c-Maf transactivates the tumor suppressor gene p53 in vitro, and overexpression of c-Maf induces apoptosis of primary cell lines via a p53-dependent mechanism [18]; however, its ability to regulate p53 in vivo appears to be cell type specific [12]. As evidenced by these studies, c-Maf is capable of activating or suppressing a diverse set of genes in a cell type-specific manner.…”

Genetic variants that affect length/height in infancy/early childhood in Vietnamese-Korean families

“…35 MAF was specifically expressed in late hypertrophic and terminal chondrocytes, as well as in osteoblasts. 36 Total long-bone length was reduced in embryos of c-MAF-null mice compared with wild-type mice. In a 4-week postnatal c-MAF-null mouse, which is almost similar to a 2-year-old child, 37 the hypertrophic chondrocyte domain was expanded in length approximately threefold compared with control littermates.…”