Wu Fashuai, Ge Chunxi, Pan Haichun, Han Yuanyuan, Mishina Yuji, Kaartinen Vesa, Franceschi Renny T
Department of Periodontics & Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Bone Res. 2025 Jan 2;13(1):7. doi: 10.1038/s41413-024-00391-z.
Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study focuses on the ability of the collagen receptor, discoidin domain receptor 2 (DDR2), to regulate BMP activity. As will be shown, induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice. In addition, Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva. In cells migrating into BMP2 implants, DDR2 is co-expressed with GLI1, a skeletal stem cell marker, and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages. Consistent with this distribution, conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals. This response was explained by selective inhibition of Gli1 cell proliferation without changes in apoptosis. The basis for this DDR2 requirement was explored further using bone marrow stromal cells. Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo, bone formation, early BMP responses including SMAD phosphorylation remained largely intact. Instead, Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates, YAP and TAZ. This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix, which subsequently affect BMP responsiveness. In summary, DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.
骨形态发生蛋白对骨再生/骨折愈合至关重要，但也可诱导异位骨化（HO）。了解调节骨形态发生蛋白信号传导的辅助因子，将为增强骨形态发生蛋白依赖性再生同时预防异位骨化提供一种方法。本研究聚焦于胶原蛋白受体盘状结构域受体2（DDR2）调节骨形态发生蛋白活性的能力。如下所示，在Ddr2基因敲除小鼠中，皮下植入骨形态发生蛋白2诱导的骨形成严重受损。此外，Ddr2基因缺陷可减轻表达与人类进行性骨化性纤维发育不良相关的ACVR1突变小鼠中的异位骨化。在迁移至骨形态发生蛋白2植入物的细胞中，DDR2与骨骼干细胞标志物GLI1共表达，且DDR2/GLI1阳性细胞参与骨形态发生蛋白2诱导的骨形成，在其中它们对软骨形成和成骨谱系有贡献。与这种分布一致，在表达Gli1的细胞中条件性敲除Ddr2抑制骨形成的程度与在整体Ddr2基因敲除动物中所见相同。这种反应是由Gli1细胞增殖的选择性抑制而非细胞凋亡的改变所解释。使用骨髓基质细胞进一步探究了这种DDR2需求的基础。尽管Ddr2基因缺陷抑制了骨形态发生蛋白2依赖性软骨细胞和成骨细胞分化以及体内骨形成，但包括SMAD磷酸化在内的早期骨形态发生蛋白反应在很大程度上仍保持完整。相反，Ddr2基因缺陷降低了Hippo信号通路中间体YAP和TAZ的核/质比。这表明DDR2调节Hippo信号通路介导的对胶原基质的反应，进而影响骨形态发生蛋白的反应性。总之，DDR2是骨形态发生蛋白信号传导的重要调节因子，是增强再生和治疗异位骨化的潜在治疗靶点。
