慢性牙周炎记忆B细胞分泌TGF-β1抑制Prx1+间充质细胞成骨分化的作用机制研究

促进牙槽骨形成作为慢性牙周炎治疗难点被人们所重视。我们前期研究发现：慢性牙周炎病人牙周组织中存在大量记忆B细胞，单细胞测序提示记忆B细胞分泌转化生长因子β1（TGF-β1），且TGF-β1中和抗体可阻断B细胞对Prx1+间充质细胞成骨分化的抑制。因此我们提出：慢性牙周炎记忆B细胞通过分泌TGF-β1，调控Smad2/3-Runx2信号轴，抑制Prx1+间充质细胞成骨分化，导致牙槽骨骨形成降低；反之，清除B细胞或去除B细胞分泌的TGF-β1，通过促进Prx1+间充质细胞成骨分化和骨形成，恢复牙槽骨量的假说。我们拟利用临床牙周组织取材，Prx1-Cre nT/nG小鼠及B细胞特异性敲除TGF-β1的小鼠牙周炎造模，通过组织、细胞、分子生物学等方法，阐明慢性牙周炎记忆B细胞分泌TGF-β1抑制Prx1+间充质细胞成骨分化的作用机制。本研究将为慢性牙周炎的靶向治疗提供新思路。

Chronic periodontitis can cause decreased alveolar bone formation, but its pathogenesis is not fully understood. Our preliminary studies showed that memory B cells were increased in the periodontal tissues of patients with chronic periodontitis. These memory B cells inhibited the osteogenic differentiation of mesenchymal cells in vitro co-culture system. Single-cell RNA-seq and transcriptional profiles by isolating single cells from periodontal tissues of chronic periodontitis patients and healthy controls indicated that memory B cells secreted transforming growth factor-β1 (TGF-β1). In addition, TGF-β1 neutralizing antibody partially rescued the inhibitory effect of memory B cells from periodontitis on the osteogenic differentiation of Prx1+ mesenchymal cells. Based on these preliminary data, we hypothesize that memory B cells of chronic periodontitis regulate Smad2/3-Runx2 signal axis by secreting TGF-β1, and inhibit the osteogenic differentiation of Prx1+ mesenchymal cells, which results in the reduction of alveolar bone formation. B cell depletion therapy or removal TGF-β1 secreted by B cells can promote bone formation and restore alveolar bone mass by promoting osteogenic differentiation of Prx1+ mesenchymal cells. We will collect periodontal tissues from patients with chronic periodontitis, generate periodontitis models by silk ligation in Prx1-Cre nT/nG mice or CD19-Cre; TGF-β1 flox/flox mice, and analyze their phenotypes using histological, cellular and molecular techniques. By better understanding the role of memory B cells in osteogenesis inhibition during periodontitis, innovative therapies may be developed that target the key immunologic pathways involved in the disease.