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Gene Review:

Fhl2 - four and a half LIM domains 2

Mus musculus

Martin, B., Günther, T., Bai, S., Du, X., Canault, M., et al.

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Disease relevance of Fhl2

Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts [1].
At 4 weeks of age, lack of FHL2 reduced femur, tibia, and total bone mineral content (BMC) and body weight in all mice [2].
FHL2 is a LIM-domain protein expressed in myoblasts but down-regulated in malignant rhabdomyosarcoma cells, suggesting an important role of FHL2 in muscle development [3].

High impact information on Fhl2

Reflecting increased RANKL sensitivity, osteoclasts generated from FHL2-/- mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts [4].
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner [4].
Fhl2 increases the transcriptional activity of runt-related transcription factor 2 (Runx2), a key regulator of osteoblast function, and both proteins interact in vitro and in vivo [1].
Our data offer a novel concept to fight osteoporosis by modulating the anabolic activity of osteoblasts via Fhl2 [1].
Osteopenia is caused by a reduced bone formation rate that is solely due to the diminished activity of Fhl2-deficient osteoblasts, while their number remains unchanged [1].

Biological context of Fhl2

To investigate the importance of FHL2 during myoblast differentiation, we performed a yeast two-hybrid screen using a cDNA library derived from myoblasts induced for differentiation [3].
Expression of FHL2 counteracts beta-catenin-mediated activation of a TCF/LEF-dependent reporter gene in a dose-dependent and muscle cell-specific manner [3].
Moreover, FHL2 coactivates transactivation of the DAX1 promoter by WT1 [5].
The importance of this interaction is revealed by the ability of FHL2 to potentiate the synergistic induction of MIS gene expression by WT1/SF1 [5].
Using the yeast two-hybrid system, we showed that ADAM-17 interacts with the Four and Half LIM domain 2 protein (FHL2), a LIM domain protein that is involved in multiple protein-protein interaction [6].

Anatomical context of Fhl2

FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro [4].
C2C12 mouse myoblasts stably expressing FHL2 show increased myogenic differentiation reflected by accelerated myotube formation and expression of muscle-specific proteins [3].
Interestingly, less ADAM-17 was detected at the surface of wild-type mouse macrophages compared to FHL2 deficient macrophages [6].

Regulatory relationships of Fhl2

After injection into Xenopus embryos, FHL2 inhibited the beta-catenin-induced axis duplication [3].

Other interactions of Fhl2

Activation of the coactivator four-and-a-half-LIM-only protein FHL2 and the c-fos promoter through inhibition of protein phosphatase 2A [7].
The ability to modulate both DAX1 and MIS expression might allow FHL2 to act in the molecular fine tuning of WT1-dependent control mechanisms in the reproductive organs [5].
FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling [4].
Here we demonstrate coexpression of the LIM-only coactivator FHL2 and WT1 [5].

Analytical, diagnostic and therapeutic context of Fhl2

Enforced expression of Fhl2 in differentiated osteoblasts boosts mineralization in cell culture and, importantly, enhances bone formation in transgenic animals [1].
FHL2-deficient mice are viable and maintain normal cardiac function both before and after acute mechanical stress induced by aortic constriction [8].

References

Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts. Günther, T., Poli, C., Müller, J.M., Catala-Lehnen, P., Schinke, T., Yin, N., Vomstein, S., Amling, M., Schüle, R. EMBO J. (2005)
Disruption of four-and-a-half LIM 2 decreases bone mineral content and bone mineral density in femur and tibia bones of female mice. Govoni, K.E., Baylink, D.J., Chen, J., Mohan, S. Calcif. Tissue Int. (2006)
The LIM-only protein FHL2 interacts with beta-catenin and promotes differentiation of mouse myoblasts. Martin, B., Schneider, R., Janetzky, S., Waibler, Z., Pandur, P., Kühl, M., Behrens, J., von der Mark, K., Starzinski-Powitz, A., Wixler, V. J. Cell Biol. (2002)
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. Bai, S., Kitaura, H., Zhao, H., Chen, J., Müller, J.M., Schüle, R., Darnay, B., Novack, D.V., Ross, F.P., Teitelbaum, S.L. J. Clin. Invest. (2005)
The LIM-only coactivator FHL2 modulates WT1 transcriptional activity during gonadal differentiation. Du, X., Hublitz, P., Günther, T., Wilhelm, D., Englert, C., Schüle, R. Biochim. Biophys. Acta (2002)
FHL2 interacts with both ADAM-17 and the cytoskeleton and regulates ADAM-17 localization and activity. Canault, M., Tellier, E., Bonardo, B., Mas, E., Aumailley, M., Juhan-Vague, I., Nalbone, G., Peiretti, F. J. Cell. Physiol. (2006)
Activation of the coactivator four-and-a-half-LIM-only protein FHL2 and the c-fos promoter through inhibition of protein phosphatase 2A. Johannessen, M., Olsen, P.A., Johansen, B., Seternes, O.M., Moens, U. Biochem. Pharmacol. (2003)
FHL2 (SLIM3) is not essential for cardiac development and function. Chu, P.H., Bardwell, W.M., Gu, Y., Ross, J., Chen, J. Mol. Cell. Biol. (2000)