mTORC1 coordinates NF-κB signaling pathway to promote chondrogenic differentiation of tendon cells in heterotopic ossification

Fu, Jiaming; Zhang, Jie; Jiang, Tao; Ao, Xiang; Lian, Zhengnan; Li, Chenglong; Zhang, Xibing; Liu, Jie; Huang, Minjun; Zhang, Zhongmin; Wang, Liang

doi:10.1016/j.bone.2022.116507

Cited by 11 publications

(19 citation statements)

References 39 publications

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“…Fu et al. recently revealed the activation of mTORC1 in the early stage of trauma‐induced HO 35 . Building upon our previous investigation, the HO formation can be influenced by pharmaceutical interventions via the mTORC1 pathway in TDSCs 7 .…”

Section: Discussionsupporting

confidence: 58%

“…34 Fu et al recently revealed the activation of mTORC1 in the early stage of trauma-induced HO. 35 Building upon our previous investigation, the HO formation can be influenced by pharmaceutical interventions via the mTORC1 pathway in TDSCs. 7 Consequently, it is suggested that MA can potentially intervene at the early stage of HO formation by modulating the mTORC1 in TDSCs, thereby preventing the progression of HO.…”

Section: Discussionmentioning

confidence: 85%

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Malvidin attenuates trauma‐induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin‐proteasome pathway

Jiang,

Ding,

Lin

et al. 2024

J Cellular Molecular Medi

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The pathogenesis of trauma‐induced heterotopic ossification (HO) in the tendon remains unclear, posing a challenging hurdle in treatment. Recognizing inflammation as the root cause of HO, anti‐inflammatory agents hold promise for its management. Malvidin (MA), possessing anti‐inflammatory properties, emerges as a potential agent to impede HO progression. This study aimed to investigate the effect of MA in treating trauma‐induced HO and unravel its underlying mechanisms. Herein, the effectiveness of MA in preventing HO formation was assessed through local injection in a rat model. The potential mechanism underlying MA's treatment was investigated in the tendon‐resident progenitor cells of tendon‐derived stem cells (TDSCs), exploring its pathway in HO formation. The findings demonstrated that MA effectively hindered the osteogenic differentiation of TDSCs by inhibiting the mTORC1 signalling pathway, consequently impeding the progression of trauma‐induced HO of Achilles tendon in rats. Specifically, MA facilitated the degradation of Rheb through the K48‐linked ubiquitination‐proteasome pathway by modulating USP4 and intercepted the interaction between Rheb and the mTORC1 complex, thus inhibiting the mTORC1 signalling pathway. Hence, MA presents itself as a promising candidate for treating trauma‐induced HO in the Achilles tendon, acting by targeting Rheb for degradation through the ubiquitin‐proteasome pathway.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 85%

Malvidin attenuates trauma‐induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin‐proteasome pathway

Jiang,

Ding,

Lin

et al. 2024

J Cellular Molecular Medi

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“…Previous studies have also shown that BMP signaling could be triggering HO (Xu et al, 2022;Kaplan and Shore, 2000). Furthermore, both mechanical stimuli and inflammation could contribute to initiate mineral deposition by activating quiescent stem cells and the mTORC1 complex (Rodgers et al, 2014;Chen et al, 2017;Fu et al, 2022). However, further investigation is required to gain a full understanding of the complex process of HO.…”

Section: Tablementioning

confidence: 99%

Heterotopic mineral deposits in intact rat Achilles tendons are characterized by a unique fiber-like structure

Pierantoni

Hammerman

Barreto

et al. 2023

Journal of Structural Biology: X

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“…10,37 Furthermore, both inflammation and mechanical loading have been suggested to contribute to HO, possibly through stimulation of mTORC1 and activation of quiescent stem cells. [38][39][40] Blocking of this pathway by rapamycin has been shown to prevent traumatic HO deposition in a mouse model for Achilles tendon injury, and could represent a possible therapeutic factor against HO. 10 Additionally, HO could result from stem cell or progenitor cell differentiation, specifically from a group of cathepsin K positive tendon progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that BMP signaling in general, and the activin receptor type‐1 (Acvr1) in particular, seem to be involved in endochondral ossification and HO 10,37 . Furthermore, both inflammation and mechanical loading have been suggested to contribute to HO, possibly through stimulation of mTORC1 and activation of quiescent stem cells 38–40 . Blocking of this pathway by rapamycin has been shown to prevent traumatic HO deposition in a mouse model for Achilles tendon injury, and could represent a possible therapeutic factor against HO 10 .…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal and microstructural characterization of heterotopic ossification in healing rat Achilles tendons

et al. 2023

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Achilles tendon rupture is a common debilitating medical condition. The healing process is slow and can be affected by heterotopic ossification (HO), which occurs when pathologic bone-like tissue is deposited instead of the soft collagenous tendon tissue. Little is known about the temporal and spatial progression of HO during Achilles tendon healing. In this study we characterize HO deposition, microstructure, and location at different stages of healing in a rat model. We use phase contrast-enhanced synchrotron microtomography, a state-of-the-art technique that allows 3D imaging at high-resolution of soft biological tissues without invasive or time-consuming sample preparation. The results increase our understanding of HO deposition, from the early inflammatory phase of tendon healing, by showing that the deposition is initiated as early as one week after injury in the distal stump and mostly growing on preinjury HO deposits. Later, more deposits form first in the stumps and then all over the tendon callus, merging into large, calcified structures, which occupy up to 10% of the tendon volume. The HOs were characterized by a looser connective trabecular-like structure and a proteoglycanrich matrix containing chondrocyte-like cells with lacunae. The study shows the potential of 3D imaging at high-resolution by phase-contrast tomography to better understand ossification in healing tendons.

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mTORC1 coordinates NF-κB signaling pathway to promote chondrogenic differentiation of tendon cells in heterotopic ossification

Cited by 11 publications

References 39 publications

Malvidin attenuates trauma‐induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin‐proteasome pathway

Malvidin attenuates trauma‐induced heterotopic ossification of tendon in rats by targeting Rheb for degradation via the ubiquitin‐proteasome pathway

Heterotopic mineral deposits in intact rat Achilles tendons are characterized by a unique fiber-like structure

Spatiotemporal and microstructural characterization of heterotopic ossification in healing rat Achilles tendons

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