TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma

Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGF beta signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration

Anti-inflammatory effect of Zanthoxylum bungeanum-cake-separated moxibustion on rheumatoid arthritis rats

Background: Zanthoxylum bungeanum-cake-separated moxibustion (ZBCS-moxi), a kind of traditional therapy of moxibustion, has been used in China since 340 B.C. However, its mechanism remains unclear. So, this study was attempted to reveal the anti-inflammatory effect of ZBCS-moxi on rheumatoid arthritis (RA) rats.Methods and Materials: Forty health SD female rats were randomly divided into 4 groups  (n=10/group): control group, model group, Zanthoxylum bungeanum-cake-separated moxibustion group (ZBCS-moxi group) and Aconitum carmichaeli-cake-separated moxibustion group (ACCS-moxi group). RA model was induced by injecting 0.1 ml Freund’s complete adjuvant (FCA) into the right hind paw of rats. Eleven days after CFA injection, the rats in ZBCS-moxi group received Zanthoxylum bungeanum- cake-separated moxibustion on Shenshu (BL23), Zusanli (ST36) acupoints and the dorsum right hind paw respectively for 3 weeks. The ACCS-moxi group was used as a positive control, while the rats were treated with Aconitum carmichaeli-cake-separated moxibustion on the same acupoints and courses. After a 3-week treatment, we investigated anti-inflammatory effect by measuring the paw volume,  observing the pathologic morphology of synovial membranes and detecting the concentration of IL-1β and TNF-α in serum.Results: Compared to model group, the swollen paw volumes, the synovial hyperplasia and pannus formation of synovial membranes and the concentration of IL-1β and TNF-α in serum decreased obviously (P<0.01, P<0.05) in ZBCS-moxi group, as well as in ACCS-moxi group. However, the swollen paw volumes, the synovial hyperplasia and pannus formation of synovial membranes and the concentration of IL-1β and TNF-α in serum in ZBCS-moxi and ACCS-moxi group did not show significant differences (P>0.05)Conclusions: ZBCS-moxi displays anti-inflammatory effect on RA rats via suppressing the expression of cytokines and has similar effect to ACCS-moxi.Key words: Anti-inflammatory effect; Zanthoxylum bungeanum-cake-separated moxibustion; Aconitum carmichaeli-cake-separated moxibustion; Rheumatoid Arthritis

Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation

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Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair

: Progenitor cells from adipose tissue are able to induce bone repair; however, inconsistent or unreliable efficacy has been reported across preclinical and clinical studies. Soluble inhibitory factors, such as the secreted Wnt signaling antagonists Dickkopf-1 (DKK1), are expressed to variable degrees in human adipose-derived stem cells (ASCs), and may represent a targetable "molecular brake" on ASC mediated bone repair. Here, anti-DKK1 neutralizing antibodies were observed to increase the osteogenic differentiation of human ASCs in vitro, accompanied by increased canonical Wnt signaling. Human ASCs were next engrafted into a femoral segmental bone defect in NOD-Scid mice, with animals subsequently treated with systemic anti-DKK1 or isotype control during the repair process. Human ASCs alone induced significant but modest bone repair. However, systemic anti-DKK1 induced an increase in human ASC engraftment and survival, an increase in vascular ingrowth, and ultimately improved bone repair outcomes. In summary, anti-DKK1 can be used as a method to augment cell-mediated bone regeneration, and could be particularly valuable in the contexts of impaired bone healing such as osteoporotic bone repair

ANTI-INFLAMMATORY EFFECT OF ZANTHOXYLUM BUNGEANUM-CAKE-SEPARATED MOXIBUSTION ON RHEUMATOID ARTHRITIS RATS

Background: Zanthoxylum bungeanum-cake-separated moxibustion (ZBCS-moxi), a kind of traditional therapy of moxibustion, has been used in China since 340 B.C. However, its mechanism remains unclear. So, this study was attempted to reveal the anti-inflammatory effect of ZBCS-moxi on rheumatoid arthritis (RA) rats. Methods and Materials: Forty health SD female rats were randomly divided into 4 groups (n=10/group): control group, model group, Zanthoxylum bungeanum-cake-separated moxibustion group (ZBCS-moxi group) and Aconitum carmichaeli-cake-separated moxibustion group (ACCS-moxi group). RA model was induced by injecting 0.1 ml Freund’s complete adjuvant (FCA) into the right hind paw of rats. Eleven days after CFA injection, the rats in ZBCS-moxi group received Zanthoxylum bungeanum- cake-separated moxibustion on Shenshu (BL23), Zusanli (ST36) acupoints and the dorsum right hind paw respectively for 3 weeks. The ACCS-moxi group was used as a positive control, while the rats were treated with Aconitum carmichaeli-cake-separated moxibustion on the same acupoints and courses. After a 3-week treatment, we investigated anti-inflammatory effect by measuring the paw volume, observing the pathologic morphology of synovial membranes and detecting the concentration of IL-1β and TNF-α in serum. Results: Compared to model group, the swollen paw volumes, the synovial hyperplasia and pannus formation of synovial membranes and the concentration of IL-1β and TNF-α in serum decreased obviously (

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

: 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

Study on Surrounding Rock Control and Support Stability of Ultra-Large Height Mining Face

Surrounding rock control and support stability in the process of coal seam mining in ultra-large height mining face are the key to normal mine operation. In this study, the roof movement and deformation of an ultra-large height mining face are analyzed, and the working resistance of the ultra-large height mining face is obtained by introducing the equivalent immediate roof. By analyzing the coal wall spalling, the multiple positions of the spalling and the required support force of the support are obtained. At the same time, ultra-large height supports are more prone to instability problems. In this study, the stability of the ultra-large height supports was analyzed by establishing a mechanical model. The results show that: 1. The overturning limit angle of support has a hyperbolic relationship with the center of gravity. 2. Under the condition of ultra-large height, the increase in the base width of the bracket significantly improves the stability of the supports. 3. The sliding limit angle of support is positively correlated with the support load and the friction coefficient between the support and the floor. The above conclusions can provide guidance on the selection of supports and the adoption of measures to enhance the stability of the supports during use under ultra-large height conditions. The working resistance of the ultra-large height supports in the 108 mining face of the Jinjitan Coal Mine was monitored. The monitoring results show that: The average resistance of the supports is 22.6 MPa. The selected supports can meet the stability requirements of the working face support. The frequency of mining resistance in 0~5 MPa accounts for 28.38%, which indicates that some supports are insufficient for the initial support force during the moving process. Furthermore, the stability of the supports can be enhanced by adjusting the moving process. This study provides a reference for the selection of supports in ultra-large height mining faces and proposes measures to enhance the stability of the supports, which provides guidance for the safe mining of coal in ultra-large height mining faces

Study on Surrounding Rock Control and Support Stability of Ultra-Large Height Mining Face

Surrounding rock control and support stability in the process of coal seam mining in ultra-large height mining face are the key to normal mine operation. In this study, the roof movement and deformation of an ultra-large height mining face are analyzed, and the working resistance of the ultra-large height mining face is obtained by introducing the equivalent immediate roof. By analyzing the coal wall spalling, the multiple positions of the spalling and the required support force of the support are obtained. At the same time, ultra-large height supports are more prone to instability problems. In this study, the stability of the ultra-large height supports was analyzed by establishing a mechanical model. The results show that: 1. The overturning limit angle of support has a hyperbolic relationship with the center of gravity. 2. Under the condition of ultra-large height, the increase in the base width of the bracket significantly improves the stability of the supports. 3. The sliding limit angle of support is positively correlated with the support load and the friction coefficient between the support and the floor. The above conclusions can provide guidance on the selection of supports and the adoption of measures to enhance the stability of the supports during use under ultra-large height conditions. The working resistance of the ultra-large height supports in the 108 mining face of the Jinjitan Coal Mine was monitored. The monitoring results show that: The average resistance of the supports is 22.6 MPa. The selected supports can meet the stability requirements of the working face support. The frequency of mining resistance in 0~5 MPa accounts for 28.38%, which indicates that some supports are insufficient for the initial support force during the moving process. Furthermore, the stability of the supports can be enhanced by adjusting the moving process. This study provides a reference for the selection of supports in ultra-large height mining faces and proposes measures to enhance the stability of the supports, which provides guidance for the safe mining of coal in ultra-large height mining faces