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