School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol BS8 1TD, UK.
Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS10 5FN, UK.
Biomolecules. 2021 Feb 13;11(2):277. doi: 10.3390/biom11020277.
Osteoporosis and other conditions associated with low bone density or quality are highly prevalent, are increasing as the population ages and with increased glucocorticoid use to treat conditions with elevated inflammation. There is an unmet need for therapeutics which can target skeletal precursors to induce osteoblast differentiation and osteogenesis. Genes associated with high bone mass represent interesting targets for manipulation, as they could offer ways to increase bone density. A damaging mutation in has recently been associated with high bone mass. Here we show that Smad9 labels groups of osteochondral precursor cells, which are not labelled by the other Regulatory Smads: Smad1 or Smad5. We show that Smad9 cells are proliferative, and that the Smad9 pocket expands following osteoblast ablation which induced osteoblast regeneration. We further show that treatment with retinoic acid, prednisolone, and dorsomorphin all alter Smad9 expression, consistent with the effects of these drugs on the skeletal system. Taken together these results demonstrate that Smad9 cells represent an undifferentiated osteochondral precursor population, which can be manipulated by commonly used skeletal drugs. We conclude that Smad9 represents a target for future osteoanabolic therapies.
骨质疏松症和其他与低骨密度或骨质量相关的疾病发病率很高，随着人口老龄化和糖皮质激素的使用增加，用于治疗炎症升高的疾病，这些疾病的发病率也在增加。对于能够针对骨骼前体细胞诱导成骨细胞分化和骨生成的治疗方法存在未满足的需求。与高骨量相关的基因是一个有趣的操作靶点，因为它们可以提供增加骨密度的方法。最近，一个破坏性突变与高骨量有关。在这里，我们发现 Smad9 标记了一群软骨前体细胞，这些细胞不被其他调控 Smad（Smad1 或 Smad5）标记。我们发现 Smad9 细胞具有增殖性，并且在诱导成骨细胞再生的成骨细胞消融后 Smad9 口袋扩张。我们进一步表明，视黄酸、泼尼松龙和 Dorsomorphin 的治疗均改变了 Smad9 的表达，这与这些药物对骨骼系统的影响一致。综上所述，这些结果表明 Smad9 细胞代表了一种未分化的软骨前体细胞群，可以通过常用的骨骼药物进行操作。我们得出结论，Smad9 代表了未来骨合成治疗的一个靶点。
