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

Abstract

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

Hydrogen Ion Capturing Hydrogel Microspheres for Reversing Inflammaging

“…To guide NPCs to a regenerate state, we engineered the all combined GelMA microspheres composed of both CAT and TGF‐ β , named GMNP, with the ability of direct transformation of cells. [ 18 ] To demonstrate the effect of TGF‐ β , GMNP CAT was also used as a comparison. First, PCR was used to verify changes in mRNA levels in cells.…”

In silico modeling the potential clinical effect of growth factor treatment on the metabolism of human nucleus pulposus cells

“…Another possible explanation for the donor variability and lack of response to GDF‐5 stimulation could be related to the expression of the BMPR2 receptor, to which GDF‐5 preferentially binds. BMPR2 activation attenuates the SMAD/TGF‐β pathway, a driver of regenerative processes in the disc, 80 with GAG synthesis shown to be regulated via SMAD2/3 in NP cells. 81 The significantly diminished expression of BMPR2 observed in Donor 1 (monolayer) and Donor 2 (monolayer and 3D) could suggest a mechanism behind the low GAG and collagen synthesis rates following GDF‐5 stimulation and the lack of predicted therapeutic outcomes in both donors.…”

Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes

“…Recently, Li et al ( 18 ) have demonstrated that the expression of TGFβRII receptor in articular cartilage decreased as early as 3 days after DMM surgery in mice, which may result in reduced combination and activation of TGFβRII and TGFβRI and further cause low activity as a kinase for p-SMAD2. Additionally, though the protein phosphorylation level of SMAD2 is mainly controlled by the kinases and phosphatases, it could also be directly degraded by ubiquitination and proteolysis under certain conditions ( 32 , 33 ). Hence, the decreased phosphorylation level of SMAD2 in the early stage might be mainly explained by the decreased kinase activity or increased degradation.…”