Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) play important roles in bone metabolism. Smad ubiquitination regulatory factors (Smurfs) regulate TGF-β/BMP signaling via ubiquitination, resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling. Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling, its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated. In the present study, we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism. Absorbable collagen sponges containing 3 μg of recombinant human BMP2 (rhBMP2) were implanted in the dorsal muscle pouches of wild type (WT) and Smurf2^−/− mice. The rhBMP2-induced ectopic bone in Smurf2^−/− mice showed greater bone mass, higher mineral apposition and bone formation rates, and greater osteoblast numbers than the ectopic bone in WT mice. In WT mice, the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone. In contrast, in Smurf2^−/− mice, the induced bone consisted of a thick, continuous outer cortical shell and abundant inner trabecular bone. Additionally, rhBMP2-stimulated bone marrow stromal cells (BMSCs) from Smurf2^−/− mice showed increased osteogenic differentiation. Smurf2 induced the ubiquitination of Smad1/5. BMP/Smad signaling was enhanced in Smurf2^−/− BMSCs stimulated with rhBMP2, and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs. These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling, thereby identifying a new regulatory mechanism in bone metabolism.

转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）在骨骼代谢中起重要作用。Smad泛素化调节因子（Smurfs）通过泛素化调节TGF-β/ BMP信号传导，导致信号传导分子降解，从而防止TGF-β/ BMP信号传导过度激活。尽管已显示Smurf2负调节TGF-β/ Smad信号传导，但尚未深入研究其在骨代谢中对BMP / Smad信号传导的参与。在本研究中，我们试图评估Smurf2在骨代谢中BMP / Smad信号传导中的作用。将包含3μg重组人BMP2（rhBMP2）的可吸收胶原海绵植入野生型（WT）和Smurf2 ^-/-小鼠的背肌袋中。rhBMP2诱导的Smurf2异位骨^{- /-}小鼠比野生型小鼠具有更大的骨量，更高的矿物质沉积和骨形成速率以及更大的成骨细胞数量。在野生型小鼠中，异位骨由不连续的薄皮质外壳和内部小梁骨组成。相反，在Smurf2 ^-/-小鼠中，诱导的骨由厚的连续皮层外皮和丰富的小梁内骨组成。此外，rhBMP2 -刺激的骨髓基质细胞（BMSCs）从SMURF2 ^{- / -}小鼠显示增加的成骨分化。Smurf2诱导Smad1 / 5的泛素化。BMP / Smad信号在Smurf2中增强^-/-用rhBMP2刺激的BMSC，并且BMP / Smad信号转导的抑制抑制了这​​些BMSC的成骨分化。这些发现表明，Smurf2负调节BMP / Smad信号传导，从而确定了骨代谢的新调节机制。