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

Autoři	ZIEBA J. FORLENZA K. N. HEARD K. MARTIN J. H. BOSÁKOVÁ Michaela COHN D. H. ROBERTSON S. P. KREJČÍ Pavel KRAKOW D.
Rok publikování	2022
Druh	Článek v odborném periodiku
Časopis / Zdroj	Bone research
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.nature.com/articles/s41413-022-00200-5
Doi	http://dx.doi.org/10.1038/s41413-022-00200-5
Klíčová slova	Spondylocarpotarsal syndrome; TGF beta/BMP signaling modulation; mouse model
Popis	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 TGFß/BMP signaling pathway that included increased canonical TGFß and noncanonical BMP signaling. In this study, the role of FLNB in the TGFß/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 TGFß/BMP signaling and that loss of FLNB produces increased TGFß receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFß/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFß/BMP pathway activity restored Flnb-/- IVD morphology. These most effective improvements resulted from specific inhibition of TGFß and p38 signaling activation. FLNB acts as a bridge for TGFß/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFß/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.