| First Author | Zieba J | Year | 2022 |
| Journal | Bone Res | Volume | 10 |
| Issue | 1 | Pages | 37 |
| PubMed ID | 35474298 | Mgi Jnum | J:325283 |
| Mgi Id | MGI:7284468 | Doi | 10.1038/s41413-022-00200-5 |
| Citation | Zieba J, et al. (2022) Intervertebral disc degeneration is rescued by TGFbeta/BMP signaling modulation in an ex vivo filamin B mouse model. Bone Res 10(1):37 |
| abstractText | Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFbeta/BMP signaling pathway that included increased canonical TGFbeta and noncanonical BMP signaling. In this study, the role of FLNB in the TGFbeta/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFbeta/BMP signaling and that loss of FLNB produces increased TGFbeta receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFbeta/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFbeta/BMP pathway activity restored Flnb(-/-) IVD morphology. These most effective improvements resulted from specific inhibition of TGFbeta and p38 signaling activation. FLNB acts as a bridge for TGFbeta/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFbeta/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders. |
