Discoidin domain receptor 2, a novel regulator of bone regeneration

由创伤、肿瘤、先天缺陷或牙周病引起的骨丢失是 残疾和人类痛苦。目前治疗骨丢失的外科方法的局限性是 促进了组织工程(TE)骨再生策略的发展，涉及各种 骨诱导性生物可降解支架。在一种方法中，开发了含有多肽的TE支架 模拟细胞外基质分子，如胶原蛋白。这些多肽与整合素受体结合在一起 骨骼祖细胞表面。然而，祖细胞也通过盘状结构域与胶原相互作用 受体2(DDR2)，是一种研究较少但很重要的胶原受体，对骨形成是必不可少的。我们的 初步研究表明，DDR2对颅骨亚临界大小的缺损和 胫骨骨折。这表明了DDR2在骨再生中的新作用，并表明基于DDR2的 治疗学可能成为一类新的骨再生剂。为此，一种三螺旋多肽包括 胶原蛋白的DDR结合域结合/激活DDR2并刺激成骨细胞分化。基于 这些令人兴奋的数据，我们提出了以下假设：DDR2是骨再生的关键因素；刺激其 通过调节其水平或使用含有DDR2结合肽的支架进行活性将是积极的 刺激骨骼再生。DDR2通过与胶原结合整合素一起作用刺激再生 诱导骨骼祖细胞向成骨细胞分化。 研究将通过实现以下目标来开发这一令人兴奋的新领域： 1.确定DDR2在骨再生中的需求。获得和失去功能的方法将是 用于评估颅面再生术中对DDR2的需求。 2.开发和评价含有DDR2和整合素激活肽的骨再生支架。 DDR2结合肽单独及与整合素结合肽联合使用的可行性 纳米纤维中空微球TE支架将在颅面再生模型中进行评估。 预期结果包括：1)展示了DDR2在#年骨骼再生中的功能作用 体内，2)确定DDR2和整合素激活肽在成骨细胞过程中是否存在串扰 差异，3)完整的“原则证明”研究显示了DDR2激活支架的价值 骨TE应用。研究将支持未来旨在开发基于DDR2的疗法的项目。

Bone loss caused by trauma, neoplasia, congenital defects or periodontal disease is a major cause of disability and human suffering. The limitations of current surgical approaches to treating bone loss have stimulated the development of tissue engineering (TE) strategies for bone regeneration involving a variety of osteoinductive biodegradable scaffolds. In one approach, TE scaffolds were developed containing peptides that mimic extracellular matrix molecules such as collagen. These peptides bind integrin receptors on the surface of skeletal progenitor cells. However, progenitors also interact with collagen via discoidin domain receptor 2 (DDR2), an understudied but important collagen receptor that is essential for bone formation. Our preliminary studies shown DDR2 to also be essential for regeneration of calvarial sub-critical-size defects and tibial fractures. This demonstrates a novel role for DDR2 in bone regeneration and suggests that DDR2-based therapeutics could be a new class of bone regeneration agents. To this end, a triple-helical peptide comprising the DDR binding domain of collagen binds/activates DDR2 and stimulates osteoblast differentiation. Based on these exciting data, we propose the following hypothesis: DDR2 is a critical factor for bone regeneration; stimulating its activity either by regulating its levels or activity using scaffold containing DDR2-binding peptides will positively stimulate bone regeneration. DDR2 stimulates regeneration by functioning together with collagen-binding integrins to induce osteoblast differentiation in skeletal progenitor cells. Studies will develop this exciting new area by achieving the following aims: 1. Establish the requirement for DDR2 in bone regeneration. Gain and loss-of-function approaches will be used to evaluate the requirement for DDR2 in craniofacial regeneration. 2. Develop and evaluate scaffolds containing Ddr2 and integrin-activating peptides in bone regeneration. The feasibility of using DDR2-binding peptides alone and together with integrin-binding peptides in nanofibrous hollow microsphere TE scaffolds will be assessed in a craniofacial regeneration model. Expected outcomes include: 1) demonstration of a functional role for DDR2 in skeletal regeneration in vivo, 2) determine if there is cross-talk between DDR2 and integrin-activating peptides during osteoblast differentiation, 3) complete "proof-of-principle" studies showing the value of DDR2-activating scaffolds for bone TE applications. Studies will support future projects aimed at developing DDR2-based therapeutics.