Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation

Hsieh, Hsiao Hsin Sung; Agarwal, Shailesh; Cholok, David; Loder, Shawn; Kaneko, Keiko; Huber, Amanda K.; Chung, Michael T.; Ranganathan, Kavitha; Habbouche, Joe; Li, John; Butts, Jonathan; Reimer, Jonathan A.; Kaura, Arminder; Drake, James C.; Breuler, Christopher; Priest, Caitlin; Nguyen, Joe; Brownley, Cameron; Peterson, Jonathan; Ozgurel, Serra Ucer; Niknafs, Yashar S.; Li, Shuli; Inagaki, Manabu; Scott, Greig; Krebsbach, Paul H.; Longaker, Michael T.; Westover, Kenneth D.; Gray, Nathanael S.; Ninomiya‐Tsuji, Jun; Mishina, Yuji; Lévi, Benjamin

doi:10.1002/stem.2991

Cited by 11 publications

(7 citation statements)

References 39 publications

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“…Of these, a shift from TGFβ signaling activation to FGF signaling activation was most apparent in the context of surgical denervation. The importance of TGFβ signaling in experimental HO formation has been described by our group and others 44 , 52 , 53 , and a loss of mesenchymal TGFβ signaling activation among denervated tissues implicates this pathway as a putative nerve-derived growth factor that drives HO formation. The activation of FGF signaling following neurectomy may have a putative effect on suppressing an osteochondrogenic program after injury.…”

Section: Discussionsupporting

confidence: 56%

NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma

et al. 2021

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Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.

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Section: Discussionsupporting

confidence: 56%

NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma

et al. 2021

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“…Recent studies have begun to elucidate bone progenitor cells during normal bone development and repair. The process by which tissue-resident mesenchymal cells undergo aberrant osteogenic and chondrogenic differentiation, however, has yet to be defined ( Agarwal et al., 2016a , 2017a ; Chan et al., 2018 ; Comazzetto et al., 2019 ; Genet et al., 2015 ; Hsieh et al., 2019 ; Hwang et al., 2019 ; Matsushita et al., 2020 ; Torossian et al., 2017 ; Wang et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells

et al. 2021

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Summary Heterotopic ossification (HO) is a form of pathological cell-fate change of mesenchymal stem/precursor cells (MSCs) that occurs following traumatic injury, limiting range of motion in extremities and causing pain. MSCs have been shown to differentiate to form bone; however, their lineage and aberrant processes after trauma are not well understood. Utilizing a well-established mouse HO model and inducible lineage-tracing mouse ( Hoxa11- CreER T2 ; ROSA26-LSL-TdTomato ), we found that Hoxa11 -lineage cells represent HO progenitors specifically in the zeugopod. Bioinformatic single-cell transcriptomic and epigenomic analyses showed Hoxa11- lineage cells are regionally restricted mesenchymal cells that, after injury, gain the potential to undergo differentiation toward chondrocytes, osteoblasts, and adipocytes. This study identifies Hoxa11 -lineage cells as zeugopod-specific ectopic bone progenitors and elucidates the fate specification and multipotency that mesenchymal cells acquire after injury. Furthermore, this highlights homeobox patterning genes as useful tools to trace region-specific progenitors and enable location-specific gene deletion.

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“…Indeed, we found TAK1 inhibition in OCPs reduced their chondrogenic gene expression, suggesting that TAK1 inhibitor prevents downstream targeting of all TGF-β pathways. Additional genetic ablation of TAK1 has also been shown to mitigate HO formation in the B/T model, another tHO model [26].…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma

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et al. 2020

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Heterotopic ossification (HO) is defined as ectopic bone formation around joints and in soft tissues following trauma, particularly blast-related extremity injuries, thermal injuries, central nerve injuries, or orthopaedic surgeries, leading to increased pain and diminished quality of life. Current treatment options include pharmacotherapy with non-steroidal anti-inflammatory drugs, radiotherapy, and surgical excision, but these treatments have limited efficacy and have associated complication profiles. In contrast, small molecule inhibitors have been shown to have higher specificity and less systemic cytotoxicity. Previous studies have shown that bone morphogenetic protein (BMP) signaling and downstream non-canonical (SMAD-independent) BMP signaling mediated induction of TGF-β activated kinase-1 (TAK1) contributes to HO. In the current study, small molecule inhibition of TAK1, NG-25, was evaluated for its efficacy in limiting ectopic bone formation following a rat blast-associated lower limb trauma and a murine burn tenotomy injury model. A significant decrease in total HO volume in the rat blast injury model was observed by microCT imaging with no systemic complications following NG-25 therapy. Furthermore, tissueresident mesenchymal progenitor cells (MPCs) harvested from rats treated with NG-25 demonstrated decreased proliferation, limited osteogenic differentiation capacity, and reduced gene expression of Tac1, Col10a1, Ibsp, Smad3, and Sox2 (P < 0.05). Single cell RNA-sequencing of murine cells harvested from the injury site in a burn tenotomy injury model showed increased expression of these genes in MPCs during stages of chondrogenic differentiation. Additional in vitro cell cultures of murine tissue-resident MPCs and osteochondrogenic progenitors (OCPs) treated with NG-25 demonstrated reduced chondrogenic differentiation by 10.2-fold (P < 0.001) and 133.3-fold (P < 0.001), respectively, as well as associated reduction in chondrogenic gene expression. Induction of HO in Tak1 knockout mice demonstrated a 7.1-fold (P < 0.001) and 2.7fold reduction (P < 0.001) in chondrogenic differentiation of murine MPCs and OCPs, respectively, with reduced chondrogenic gene expression. Together, our in vivo models and in vitro cell culture studies demonstrate the importance of TAK1 signaling in chondrogenic differentiation and HO formation and suggest that small molecule inhibition of TAK1 is a promising therapy to limit the formation and progression of HO.

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Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation

Cited by 11 publications

References 39 publications

NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma

NGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma

Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells

Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma

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