The role of TGFβ target——LTBP4 in muscular dystrophy

 

Recently, a new finding was reported associated with Duchenne muscular dystrophy (DMD). Ceco et al. found latent transforming growth factor-β (TGFβ) binding proteins 4 (LTBP4) play determinant roles in muscular dystrophy symptoms. The article was published on Science Translational Medicine.

 

DMD, the loss of protein dystrophin, leads to weakness of muscle sarcolemma, muscle degeneration and eventual death. Previously studies showed the important role of LTBP4 in determination of sarcolemma fragility and fibrosis. TGFβ, which binds to LTBP4 in the extracellular matrix, is elevated in human DMD and induces muscle injury. Researcher generated transgenic mice with a bacterial artificial chromosome encoding the human LTBP4 gene. What they found was that hLTBP4 BAC transgenic mice showed myofiber hypertrophy and skeletal muscle membrane damage and fibrosis. After induced muscle injury, transgenic mice showed an increase of LTBP4 protein expression. Also, they found an enhanced TGFβ signaling by increasing drosophila mothers against decapentaplegic protein (SMAD) in hLTBP4 BAC transgenic mice. Further investigation showed shorter hinge region of LTBP4 leads to more protein proteolytic susceptibility, more TGFβ releasing and worsening of muscular dystrophy.

 

Their data suggested that blocking LTBP4 results in reduced TGFβ release, and then leads to a reduction of muscle inflammation and damage in DMD. This approach may be a promising therapeutic strategy for DMD patients.

 

Reference:
Sci Transl Med. 2014 Oct 22;6(259):ra144.

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S2230	Galunisertib (LY2157299)	Galunisertib (LY2157299) is a potent TGFβ receptor I (TβRI) inhibitor with IC50 of 56 nM in a cell-free assay. Phase 2/3.
S1476	SB525334	SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, 4-fold less potent to ALK4 than ALK5 and inactive to ALK2, 3, and 6.

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TGF-beta/Smad