Publication details

Intervertebral disc degeneration is rescued by TGF beta/BMP signaling modulation in an ex vivo filamin B mouse model


ZIEBA Jennifer FORLENZA Kimberly N HEARD Kelly MARTIN Jorge H BOSÁKOVÁ Michaela COHN Daniel H ROBERTSON Stephen P KREJČÍ Pavel KRAKOW Deborah

Year of publication 2022
Type Article in Periodical
Magazine / Source Bone research
MU Faculty or unit

Faculty of Medicine

Keywords Intervertebral disc degeneration; TGF beta/BMP signaling modulation; ex vivo filamin B mouse model
Description 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 TGF beta/BMP signaling pathway that included increased canonical TGF beta and noncanonical BMP signaling. In this study, the role of FLNB in the TGF beta/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 TGF beta/BMP signaling and that loss of FLNB produces increased TGF beta receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGF beta/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGF beta/BMP pathway activity restored Flnb(-/-) IVD morphology. These most effective improvements resulted from specific inhibition of TGF beta and p38 signaling activation. FLNB acts as a bridge for TGF beta/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGF beta/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.

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