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.

脊柱腕跗骨综合征 (SCT) 是一种罕见的肌肉骨骼疾病，其特征是身材矮小以及椎骨、腕骨和跗骨融合，这是由编码纤维蛋白 B (FLNB) 的基因双等位基因无义突变引起的。利用 FLNB 敲除小鼠，我们发现 SCT 中的椎体融合是由椎间盘 (IVD) 退变和纤维环 (AF) 骨化演变而来，最终导致完整的骨小梁形成。这是由于 TGFβ/BMP 信号通路的改变造成的，其中包括经典 TGFβ 和非经典 BMP 信号传导的增加。在这项研究中，使用体外、体内和离体治疗方法阐明了 FLNB 在 TGFβ/BMP 途径中的作用。数据表明，FLNB 与抑制性 Smads 6 和 7 (i-Smads) 相互作用来调节 TGFβ/BMP 信号传导，并且 FLNB 的缺失会导致 TGFβ 受体活性增加并降低 Smad 1 泛素化。通过在离体脊柱模型中使用小分子抑制剂，调节 TGFβ/BMP 信号传导，设计针对 SCT 和椎间盘退变的靶向治疗。抑制典型和非典型 TGFβ/BMP 通路活性可恢复Flnb ^−/− IVD 形态。这些最有效的改善源自对 TGFβ 和 p38 信号传导激活的特异性抑制。 FLNB 通过 i-Smads 作为 TGFβ/BMP 信号串扰的桥梁，是维持 IVD 的 TGFβ/BMP 信号关键平衡的关键。这些发现进一步加深了我们对 IVD 生物学的理解，并揭示了椎间盘退变和先天性椎体融合障碍的新分子靶标。