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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language 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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

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

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2022

Confidentiality

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

Name of the periodical

Bone Research

ISSN

2095-4700

e-ISSN

2095-6231

Volume of the periodical

10

Issue of the periodical within the volume

1

Country of publishing house

CN - CHINA

Number of pages

12

Pages from-to

37

UT code for WoS article

000787774700001

EID of the result in the Scopus database

2-s2.0-85128943993