Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Freiburgstrasse 7, 3010 Bern, Switzerland.
Bone. 2012 Oct;51(4):800-9. doi: 10.1016/j.bone.2012.07.017. Epub 2012 Jul 28.
Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre-soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix-derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent differentiation along the osteo-chondrogenic pathway. These results indicate that BMP2 will be among the signaling molecules whose presence will determine success or failure of new bone graft strategies.
骨移植的吸收取决于宿主和移植物中众多生长因子和细胞因子的有序激活。在这个信号级联中，BMP2 最为突出。虽然 BMP2 对于骨形成不是必需的，但它是骨修复启动所必需的；因此，理解 BMP2 驱动的骨再生的细胞机制对于改善骨移植治疗至关重要。在本研究中，我们使用在骨骼形成前就已经去除了 Bmp2 的肢体中的小鼠来评估 Bmp2 在骨移植吸收中的作用（Bmp2(cKO)）。当在 Bmp2cKO 小鼠中进行自体移植时，骨痂形成和骨愈合均不存在。将活性野生型（WT）骨移植物移植到 Bmp2(cKO)宿主中，或将活性 Bmp2(cKO)移植物移植到 WT 宿主中，也导致骨移植吸收的抑制。对这些移植物的组织学分析表明，在没有 BMP2 的情况下，骨膜祖细胞保持静止，愈合不会启动。当我们分析移植物表面的软骨生成标志物 Sox9 的表达时，发现当移植物本身或宿主中没有 BMP2 时，其表达显著降低，这表明局部 BMP2 水平驱动骨膜细胞凝聚和随后的骨痂细胞分化。在没有 BMP2 的情况下，整合愈合的缺乏并不是由于骨膜细胞无法对 BMP2 作出反应。当移植物预先浸泡在 rhBMP2 蛋白中时，愈合就会发生，这表明在没有 BMP2 的情况下，骨膜祖细胞仍然有反应。与 BMP2 在活性骨移植物中激活骨膜祖细胞的要求相反，我们发现骨基质衍生的 BMP2 并不能显著增强骨移植的吸收。总之，我们的数据表明，BMP2 信号对于骨膜祖细胞的维持不是必需的，但对于这些祖细胞的激活及其随后沿成骨-软骨分化途径的分化是必需的。这些结果表明，BMP2 将是决定新骨移植策略成败的信号分子之一。
