Transforming growth factor -inducible early gene 1 (TIEG1) is a member of the Krüppel-like transcription factor family. To understand the physiological role of TIEG1, we generated TIEG ؊/؊ (null) mice and found that the TIEG ؊/؊ mice had increased osteoblast numbers with no increased bone formation parameters. However, when calvarial osteoblasts (OBs) were isolated from neonatal TIEG ؊/؊ and TIEG ؉/؉ mice and cultured in vitro, the TIEG ؊/؊ cells displayed reduced expression of important OB differentiation markers. When the OBs were differentiated in vitro by treatment with bone morphogenic protein 2, the OBs from TIEG ؉/؉ calvaria displayed several mineralized nodules in culture, whereas those from TIEG ؊/؊ mice showed no nodules. To characterize the OBs' ability to support osteoclast differentiation, the OBs from TIEG ؉/؉ and TIEG ؊/؊ mice were cultured with marrow and spleen cells from TIEG ؉/؉ mice. Significantly fewer osteoclasts developed when TIEG ؊/؊ OBs were used to support osteoclast differentiation than when TIEG ؉/؉ OBs were used. Examination of gene expression in the TIEG ؊/؊ OBs revealed decreased RANKL and increased OPG expression compared to TIEG ؉/؉ OBs. The addition of RANKL to these cocultures only partially restored the ability of TIEG ؊/؊ OBs to support osteoclast differentiation, whereas M-CSF alone or combined with RANKL had no additional effect on osteoclast differentiation. We conclude from these data that TIEG1 expression in OBs is critical for both osteoblast-mediated mineralization and osteoblast support of osteoclast differentiation.Krüppel-like transcription factors (KLFs) are DNA-binding transcriptional regulators which contain C 2 , H 2 -type zinc fingers and play important roles in regulating biological processes such as cell growth, differentiation, and embryogenesis (1, 5, 32). The number of members of the KLF family has been increasing, and it is estimated that 1% of the human genome might contain this family of regulatory factors (5, 11). Our laboratory has cloned a member of this family, the transforming growth factor  (TGF-)-inducible early gene 1 (TIEG1), since it represented a primary response gene to TGF- treatment in human osteoblasts (28). Cook et al. (4) identified TIEG2, which shares 91% homology with TIEG1 within the zinc finger region but only 44% homology at the N terminus region. They also showed evidence that overexpression of TIEG2 in Chinese hamster ovary cells inhibits cell proliferation. Recently, Wang et al. (36) identified another member of the TIEG family, TIEG3, which has properties similar to those of TIEG1 and TIEG2.A better understanding of the mechanism of action of TIEG1 is evolving. Using a GAL4-based transcriptional assay, Cook et al. (4) demonstrated that TIEG1 protein has three repression domains. Studies by Zhang et al. (39) identified an alpha-helical repression motif located within the repression domain of TIEG1 and TIEG2. These authors have also shown evidence that these motifs mediate the direct interaction of TIEG1 with mSin3A, whic...