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Frontiers of Medicine

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Front. Med.    2019, Vol. 13 Issue (5) : 575-589    https://doi.org/10.1007/s11684-019-0693-9
RESEARCH ARTICLE
Glycosylation of dentin matrix protein 1 is critical for fracture healing via promoting chondrogenesis
Hui Xue1, Dike Tao1, Yuteng Weng1, Qiqi Fan1, Shuang Zhou1, Ruilin Zhang1, Han Zhang2, Rui Yue3, Xiaogang Wang4(), Zuolin Wang1(), Yao Sun1()
1. Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China
2. School & Hospital of Stomatology, Tongji University, Shanghai 200072, China
3. School of Life Sciences and Technology, Tongji University, Shanghai 200072, China
4. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing 100083, China
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Abstract

Fractures are frequently occurring diseases that endanger human health. Crucial to fracture healing is cartilage formation, which provides a bone-regeneration environment. Cartilage consists of both chondrocytes and extracellular matrix (ECM). The ECM of cartilage includes collagens and various types of proteoglycans (PGs), which play important roles in maintaining primary stability in fracture healing. The PG form of dentin matrix protein 1 (DMP1-PG) is involved in maintaining the health of articular cartilage and bone. Our previous data have shown that DMP1-PG is richly expressed in the cartilaginous calluses of fracture sites. However, the possible significant role of DMP1-PG in chondrogenesis and fracture healing is unknown. To further detect the potential role of DMP1-PG in fracture repair, we established a mouse fracture model by using a glycosylation site mutant DMP1 mouse (S89G-DMP1 mouse). Upon inspection, fewer cartilaginous calluses and down-regulated expression levels of chondrogenesis genes were observed in the fracture sites of S89G-DMP1 mice. Given the deficiency of DMP1-PG, the impaired IL-6/JAK/STAT signaling pathway was observed to affect the chondrogenesis of fracture healing. Overall, these results suggest that DMP1-PG is an indispensable proteoglycan in chondrogenesis during fracture healing.
Keywords fracture      extracellular matrix      dentin matrix protein 1      proteoglycan      cartilage     
Corresponding Author(s): Xiaogang Wang,Zuolin Wang,Yao Sun   
Just Accepted Date: 04 April 2019   Online First Date: 09 May 2019    Issue Date: 14 October 2019
 Cite this article:   
Hui Xue,Dike Tao,Yuteng Weng, et al. Glycosylation of dentin matrix protein 1 is critical for fracture healing via promoting chondrogenesis[J]. Front. Med., 2019, 13(5): 575-589.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0693-9
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I5/575
Fig.1  Expression of DMP1-PG in cartilage callus during fracture healing. (A) H&E and Toluidine blue staining of unfractured femurs and fractured femurs is shown at days 7, 21, and 28 post-fracture in WT mice. Scale bars= 500 mm. (B) Weaker cartilaginous calluses were formed in the 12-month-old WT mice compared with those of the 3-month-old WT mice at day 7 post-fracture. Lower magnification, scale bars= 500 mm; higher magnification, scale bars= 200 mm. (C) RT-qPCR quantification of Acan, Bgn, Dcn, Vcan, and Dmp1 in the fracture calluses from normal mice and fracture model mice. Data are shown as mean±SEM. *P<0.05, n = 3 per time point. NS, not significant. (D) DMP1-F/DMP1-PG was expressed in the cartilaginous calluses of the fracture model mice. Lower magnification, scale bars= 100 mm; higher magnification, scale bars= 50 mm. (E) The expression level of DMP1-PG was downregulated in the fracture callus of the 12-month-old WT mice compared that of the 3-month-old WT mice at day 7 post-operation by Western immunoblotting. *P<0.05, n = 3 per group. 3m, 3-month-old; 12m, 12-month-old.
Fig.2  Delayed femur fracture healing in S89G-DMP1 mice. (A) A schematic of the DMP1-PG point mutation model is shown. (B) Decreased DMP1-PG expression in the fracture callus of the S89G-DMP1 mice is shown at day 7 post-fracture by Western immunoblotting. (C) Representative three-dimensional reconstruction of micro-CT images of fracture sites at days 7, 14, 21, and 28 post-fracture. Arrows show the fracture gaps and calluses. (D) The quantitative micro-CT analysis of fracture callus is shown as mean±SEM. *P<0.05, n = 5 per group per time point. BV/TV, callus bone volume; BMD, bone mineral density; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular space. (E) Biomechanical testing of the fractured femurs displaying the impaired mechanical property of the new bone in S89G-DMP1 mice at day 28 post-fracture. *P<0.05, n = 5 per group per time point.
Fig.3  Histological analysis of the femur fracture healing in WT and S89G-DMP1 mice. (A) H&E, Toluidine blue, and Safranin O staining of fracture calluses showed small cartilaginous calluses and new bone calluses in S89G-DMP1 mice. Scale bars= 500 mm. (B) Quantification of cartilaginous callus areas from (A) is shown as mean±SEM. *P<0.05, n = 5 per group per time point. (C) Quantification of new bone callus areas from (A) is shown as mean±SEM. *P<0.05, n = 5 per group per time point.
Fig.4  Alterations of cartilage markers in the cartilaginous calluses of the WT and S89G-DMP1 mice. (A1–A6, B1–B6) Immunohistochemistry staining of COL-II, COL-X, SOX9, ACAN, DCN, and VCAN in cartilaginous callus at day 7 post-fracture. Samples from S89G-DMP1 mice showed remarkably decreased immunoreactivity. Scale bars= 100 mm. (C1–C6) Quantitative measurements of the positive zone area/total callus area or the number of positive cells/number of total cells from the WT and S89G-DMP1 mice are shown as mean±SEM. *P<0.05, n = 4 per group. (D1–D6) RT-qPCR quantification analysis of Col-II, Col-X, Sox9 Acan, Dcn, and Vcan is presented as mean±SEM. *P<0.05, n = 4–5 per group per time point.
Fig.5  BMSCs differentiation, proliferation, and migration of WT and S89G-DMP1 mice. (A) Comparison of cultured aggregates from WT and S89G-DMP1 mice is shown by Toluidine blue staining. Scale bars= 1500 mm. (B) The mRNA levels of chondrogenesis-related genes and proteoglycan genes were determined by RT-qPCR. *P<0.05, n = 3 samples per group. (C) A CCK8 assay was performed to analyze the proliferation ability of BMSCs. *P<0.05, n = 5 samples per group. (D) Representative images of Transwell migration assay of BMSCS from the WT group and the S89G-DMP1 group. (E) The quantification of invasive cells of Transwell migration assay is shown as mean±SEM. *P<0.05, n = 4 samples per group. No difference was found in the ability of migration of BMSCs between the WT and S89G-DMP1 mice.
Fig.6  Differentially expressed mRNA sequences between WT and S89G-DMP1 fracture calluses. (A) Heat map and (B) Volcano plot analysis displayed differentially expressed genes of fracture calluses between the WT and DMP1-S89G mice. KEGG analysis showed the top ten upregulated (C) and downregulated (D) signaling pathways of fracture calluses in S89G-DMP1 mice compared with WT mice.
Fig.7  Detection of IL-6/JAK/STAT signaling in the WT and S89G-DMP1 mice. (A) RT-qPCR quantification of inflammatory molecules during fracture healing is shown as mean±SEM. *P<0.05, n = 6 per group per time point. (B) IL-6 (green) immunofluorescence staining of fracture sites at days 1 and 3 post-fracture. Arrows showed the fracture ends. Lower magnification, scale bars= 500 mm; higher magnification, scale bars= 200 mm. (C) RT-qPCR quantification of JAK/STAT signaling molecules JAK-2 and STAT-3 in the fracture calluses at days 1 and 3 post-fracture is shown as mean±SEM. *P<0.05, n = 4 per group per time point. (D) Expression of phosphorylated STAT-3 was downregulated in the fracture site in S89G-DMP1 mice by Western immunoblotting. *P<0.05, n = 3 per group per time point. (E) Loss of DMP1-PG affected chondrogenesis in fracture healing.
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