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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F22%3A00557273" target="_blank" >RIV/67985904:_____/22:00557273 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00159816:_____/22:00077625 RIV/00216224:14110/22:00128436

Výsledek na webu

<a href="https://www.nature.com/articles/s41413-022-00200-5" target="_blank" >https://www.nature.com/articles/s41413-022-00200-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41413-022-00200-5" target="_blank" >10.1038/s41413-022-00200-5</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bone Research

ISSN

2095-4700

e-ISSN

2095-6231

Svazek periodika

10

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

CN - Čínská lidová republika

Počet stran výsledku

12

Strana od-do

37

Kód UT WoS článku

000787774700001

EID výsledku v databázi Scopus

2-s2.0-85128943993