Institute for Macromolecular Chemistry, University of Freiburg, 79104 Freiburg, Germany.
BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6135-E6144. doi: 10.1073/pnas.1805159115. Epub 2018 Jun 18.
In adult bone injuries, periosteum-derived mesenchymal stem/stromal cells (MSCs) form bone via endochondral ossification (EO), whereas those from bone marrow (BM)/endosteum form bone primarily through intramembranous ossification (IMO). We hypothesized that this phenomenon is influenced by the proximity of MSCs residing in the BM to the trabecular bone microenvironment. Herein, we investigated the impact of the bone mineral phase on human BM-derived MSCs' choice of ossification pathway, using a biomimetic bone-like hydroxyapatite (BBHAp) interface. BBHAp induced hyperstimulation of extracellular calcium-sensing receptor (CaSR) and temporal down-regulation of parathyroid hormone 1 receptor (PTH1R), leading to inhibition of chondrogenic differentiation of MSCs even in the presence of chondroinductive factors, such as transforming growth factor-β1 (TGF-β1). Interestingly rescuing PTH1R expression using human PTH fragment (1-34) partially restored chondrogenesis in the BBHAp environment. In vivo studies in an ectopic site revealed that the BBHAp interface inhibits EO and strictly promotes IMO. Furthermore, CaSR knockdown (CaSR KD) disrupted the bone-forming potential of MSCs irrespective of the absence or presence of the BBHAp interface. Our findings confirm the expression of CaSR in human BM-derived MSCs and unravel a prominent role for the interplay between CaSR and PTH1R in regulating MSC fate and the choice of pathway for bone formation.
在成人骨骼损伤中，骨膜来源的间充质干细胞/基质细胞 (MSCs) 通过软骨内骨化 (EO) 形成骨骼，而骨髓 (BM)/骨内膜来源的 MSCs 主要通过膜内骨化 (IMO) 形成骨骼。我们假设这种现象受到 BM 中 MSCs 与骨小梁微环境接近程度的影响。在此，我们使用仿生骨样羟基磷灰石 (BBHAp) 界面研究了骨矿物质相对人 BM 来源 MSCs 选择成骨途径的影响。BBHAp 诱导细胞外钙敏感受体 (CaSR) 过度刺激和甲状旁腺激素 1 受体 (PTH1R) 的暂时下调，导致即使存在软骨诱导因子（如转化生长因子-β1 (TGF-β1)），MSC 的软骨分化也受到抑制。有趣的是，使用人甲状旁腺激素片段 (1-34) 恢复 PTH1R 表达可部分恢复 BBHAp 环境中的软骨生成。异位部位的体内研究表明，BBHAp 界面抑制 EO 并严格促进 IMO。此外，CaSR 敲低 (CaSR KD) 破坏了 MSCs 的成骨潜力，无论 BBHAp 界面的存在与否。我们的研究结果证实了 CaSR 在人 BM 来源 MSCs 中的表达，并揭示了 CaSR 和 PTH1R 之间的相互作用在调节 MSC 命运和骨形成途径选择方面的重要作用。
