Characterization of Netrin-1 and Its Receptors UNC5B and Neogenin-1 in a Rat Rotator Cuff Tear Model: Associations with Inflammatory Mediators and Neurite Extension
Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has b...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
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| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/47/7/511 |
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| Summary: | Rotator cuff tears are a leading cause of shoulder pain and dysfunction, yet the molecular mechanisms that link tendon injury to inflammation and nociceptive signaling remain poorly understood. Netrin-1, a classical axon guidance cue signaling through dependence receptors UNC5B and Neogenin-1, has been implicated in both neuronal plasticity and inflammatory processes, but its role in tendon pathology has not been explored. A rat supraspinatus tear model was employed to assess, in vivo, the expression of genes encoding netrin-1 (<i>Ntn1</i>) and its receptors (<i>Unc5b</i> and <i>Neo1</i>) at 0, 7, 14, 28, and 56 days post-injury (n = 10 per time point). Primary rat tenocytes isolated from rotator cuff tissue were treated in vitro with recombinant netrin-1, and transcriptional changes in genes encoding TNF-α (<i>Tnfa</i>), IL-6 (<i>Il6</i>), MMP-1 (<i>Mmp1</i>), and MMP-3 (<i>Mmp3</i>) were quantified by qRT-PCR. Separately, human iPSC-derived sensory neurons were exposed to netrin-1, and dose- and time-dependent effects on neurite outgrowth were measured at 4 and 14 days in culture. In injured tendons, <i>Ntn1</i> mRNA increased significantly at day 14 (<i>p</i> = 0.010) and 28 (<i>p</i> = 0.042), <i>Unc5b</i> at day 7 (<i>p</i> = 0.002) and 14 (<i>p</i> < 0.001), and <i>Neo1</i> at day 14 (<i>p</i> < 0.001) versus intact controls. Tenocyte exposure to 500 ng/mL netrin-1 induced transient upregulation of <i>Tnfa</i> (3 h, <i>p</i> = 0.023; 6 h, <i>p</i> = 0.009) and <i>Il6</i> (3 h–24 h, all <i>p</i> < 0.013), as well as <i>Mmp3</i> (3–24 h, <i>p</i> < 0.043) and <i>Mmp1</i> (6 h–24 h, <i>p</i> < 0.024); no induction was observed at 50 ng/mL. In sensory neurons, 50 ng/mL of netrin-1 enhanced neurite extension at day 4 (<i>p</i> = 0.006) but not at 500 ng/mL or at day 14 for either dose. Netrin-1 and its receptors are upregulated in a rat rotator cuff tear model, and netrin-1 elicits distinct pro-inflammatory and matrix-remodeling responses in tenocytes while promoting early neurite growth in sensory neurons. These findings suggest netrin-1 as a key modulator of tendon inflammation, matrix turnover, and peripheral nerve plasticity following injury. |
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| ISSN: | 1467-3037 1467-3045 |