Mast cell activation by NGF drives the formation of trauma-induced heterotopic ossification
Tao Jiang, Xiang Ao, Xin Xiang, Jie Zhang, Jieyi Cai, Jiaming Fu, Wensheng Zhang, Zhenyu Zheng, Jun Chu, Minjun Huang, Zhongmin Zhang, Liang Wang
Tao Jiang, Xiang Ao, Xin Xiang, Jie Zhang, Jieyi Cai, Jiaming Fu, Wensheng Zhang, Zhenyu Zheng, Jun Chu, Minjun Huang, Zhongmin Zhang, Liang Wang
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Research Article Bone biology Immunology

Mast cell activation by NGF drives the formation of trauma-induced heterotopic ossification

Abstract

Soft tissue trauma can cause immune system disturbance and neuropathological invasion, resulting in heterotopic ossification (HO) due to aberrant chondrogenic differentiation of mesenchymal stem cells (MSCs). However, the molecular mechanisms behind the interaction between the immune and nervous systems in promoting HO pathogenesis are unclear. In this study, we found that mast cell–specific deletion attenuated localized tissue inflammation, with marked inhibition of HO endochondral osteogenesis. Likewise, blockage of nerve growth factor (NGF) receptor, known as tropomyosin receptor kinase A (TrkA), led to similar attenuations in tissue inflammation and HO. Moreover, while NGF/TrkA signaling did not directly affect MSCs chondrogenic differentiation, it modulated mast cell activation in traumatic soft tissue. Mechanistically, lipid A in LPS binding to TrkA enhanced NGF-induced TrkA phosphorylation, synergistically stimulating mast cells to release neurotrophin-3 (NT3), thereby promoting MSC chondrogenic differentiation in situ. Finally, analysis of single-cell datasets and human pathological specimens confirmed the important role of mast cell–mediated neuroinflammation in HO pathogenesis. In conclusion, NGF regulates mast cells in soft tissue trauma and drives HO progression via paracrine NT3. Targeted early inhibition of mast cells holds substantial promise for treating traumatic HO.

Authors

Tao Jiang, Xiang Ao, Xin Xiang, Jie Zhang, Jieyi Cai, Jiaming Fu, Wensheng Zhang, Zhenyu Zheng, Jun Chu, Minjun Huang, Zhongmin Zhang, Liang Wang

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Figure 1

Mast cell deficiency inhibits pathological endochondral osteogenesis.

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Mast cell deficiency inhibits pathological endochondral osteogenesis. (A...
(A) Representative μCT 3D modeling images of Achilles tendon (sagittal view) in the indicated groups 4 weeks (cartilaginous phase), 8 weeks (ossification phase), or 12 weeks (osseous phase) after tenotomy. Red dashed ovals represent ectopic bones. Scale bar: 2 mm. (B and C) Representative images for Masson’s staining (cartilage [blue], heterotopic bone and Achilles tendon [red]) and SOFG staining (cartilage [red], heterotopic bone and Achilles tendon [green]) of injured tendon sections in the indicated groups after tenotomy. Scale bar: 5 μm. (D–G) Representative IF staining for SOX9 (red), COL2A1 (green), RUNX2 (red), and OCN (green) of injured tendon sections in the indicated groups after tenotomy, with DAPI counterstaining (blue). Scale bar: 5 μm. (H and I) Representative quantification of A and Supplemental Figure 6, showing ectopic bone volume (BV) and bone surface area (BA) in the indicated groups after tenotomy. n = at least 8 biological replicates. (J and K) Representative quantification of A and B, showing the percentage of neosynthetic pathological collagen (NPC) and cartilage matrix (CM) in injured tendon sections from the indicated groups after tenotomy. n = 5 biological replicates. (L–O) Representative quantification of D–G, showing the positive areas of SOX9, COL2A1, RUNX2, and OCN in injured tendon sections from the indicated groups after tenotomy. n = 5 biological replicates. All data are representative of 2 independent experiments. Data were shown as mean ± SD and compared with 2-tailed unpaired Student’s t test (H and I) or 2-way ANOVA with Šídák’s multiple comparisons test (J–O).