Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.
Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong, SAR, China.
Nat Commun. 2018 Aug 24;9(1):3428. doi: 10.1038/s41467-018-05974-z.
Bone morphogenetic protein (BMP) signaling is essential for osteogenesis. However, recombinant human BMPs (rhBMPs) exhibit large inter-individual variations in local bone formation during clinical spinal fusion. Smurf1 ubiquitinates BMP downstream molecules for degradation. Here, we classify age-related osteoporosis based on distinct intraosseous BMP-2 levels and Smurf1 activity. One major subgroup with a normal BMP-2 level and elevated Smurf1 activity (BMP-2/Smurf1) shows poor response to rhBMP-2 during spinal fusion, when compared to another major subgroup with a decreased BMP-2 level and normal Smurf1 activity (BMP-2/Smurf1). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy)acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2/Smurf1 mice, the chalcone derivative enhances local bone formation during spinal fusion. After conjugating to an osteoblast-targeting and penetrating oligopeptide (DSS), the chalcone derivative promotes systemic bone formation in BMP-2/Smurf1 mice. This study demonstrates a precision medicine-based bone anabolic strategy for age-related osteoporosis.
骨形态发生蛋白 (BMP) 信号对于成骨作用至关重要。然而，在临床脊柱融合过程中，重组人 BMP（rhBMP）在局部骨形成方面表现出较大的个体间差异。Smurf1 可泛素化 BMP 下游分子进行降解。在此，我们根据不同的骨内 BMP-2 水平和 Smurf1 活性对与年龄相关的骨质疏松症进行分类。一个主要亚组的 BMP-2 水平正常但 Smurf1 活性升高（BMP-2/Smurf1），与另一个 BMP-2 水平降低但 Smurf1 活性正常的主要亚组（BMP-2/Smurf1）相比，在脊柱融合过程中对 rhBMP-2 的反应较差。我们筛选了一种查尔酮衍生物，即 2-(4-肉桂酰苯氧基）乙酸，它可以有效抑制 Smurf1 活性并增加 BMP 信号。对于 BMP-2/Smurf1 小鼠，查尔酮衍生物可增强脊柱融合过程中的局部骨形成。将其与一种成骨细胞靶向和穿透寡肽（DSS）偶联后，查尔酮衍生物可促进 BMP-2/Smurf1 小鼠的全身骨形成。本研究为与年龄相关的骨质疏松症提供了一种基于精准医学的骨合成治疗策略。
