A higher expression of P2X7 receptor at the site of heterotopic ossification promotes osteogenesis

2021 ◽  
Author(s):  
Shi Cheng ◽  
Pengbin Yin ◽  
Yi Li ◽  
Ming Chen ◽  
Duanyang Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Achilles Tendon ◽  
Heterotopic Ossification ◽  
P2x7 Receptor ◽  
Complex Disease ◽  
Burn Injury ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Inflammatory Condition ◽  
Ectopic Bone

Abstract Background Heterotopic ossification (HO) refers to a painful and complex disease. Adenosine triphosphate (ATP), as a key modulator of inflammation, is verified to promote the development of HO. However, the mechanism remains to be illustrated. The ionotropic P2X7 receptor (P2X7R) is an ATP-gated ion channel expressed in the majority of stem cells. Here, this paper hypothesizes that P2X7R may be activated by extracellular ATP and promote osteogenesis of stem cells under inflammatory condition, ending up in the formation of ectopic bone. Methods The tenotomy puncture and burn injury-induced HO model was constructed. The expression of P2X7R was found increasing at the site of injured Achilles tendon where HO occurs. Mesenchymal stem cells (MSCs) were cultivated under an inflammatory condition plus Bz-ATP treatment which mimicked a microenvironment of HO site. An induction in P2X7R expression was also observed along with an enhancement of osteogenesis. In addition, an inhibition of P2X7R expression by its specific antagonist successfully reversed the above process. Results P2X7R expression of the Achilles tendon and osteogenic capability of SCs is higher in HOG than in other two groups. Bz-ATP promoted osteogenesis under inflammation condition. BBG impeded the heterotopic bone formation in animal model. Conclusions P2X7R is a crucial mediator in ATP-signaling promotion of HO, blocking which may represent a potential therapeutic target for HO.

scholarly journals Role of the P2X7 Receptor in the Osteogenesis of Heterotopic Ossification of the Achilles Tendon

2022 ◽  
Author(s):  
Shi Cheng ◽  
Siqi Zhang ◽  
Jinglong Yan ◽  
Songcen Lv
Keyword(s):  
Stem Cells ◽  
Bone Formation ◽  
Achilles Tendon ◽  
Heterotopic Ossification ◽  
P2x7 Receptor ◽  
Control Group ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Ectopic Ossification ◽  
Inflammatory Conditions

Abstract Background Heterotopic ossification (HO) refers to a painful and complex disease. HO occurs in the setting of persistent systemic inflammation and appears in flare-ups during inflammation, following injury. In the recent research, the P2X7 receptor (P2X7R) is tightly involved in the osteogenesis of periodontal ligament stem cells under the inflammatory conditions. The ionotropic P2X7 receptor (P2X7R) is an ATP-gated ion channel expressed in the majority of stem cells. However, the function of P2X7R in the pathological formation of HO is unclear. Here, this paper hypothesizes that in the model of Achilles tendon ectopic ossification, P2X7R is overexpressed in tendon-derived stem cells and promote osteogenesis of tendon-derived stem cells under inflammatory conditions. Methods The tenotomy puncture and burn injury-induced HO model was constructed. The qPCR and immunofluorescence were used to detect the expression of P2X7R at the site of injured Achilles tendon where HO occurs. Achilles tendon stem cells (SCs) from control group and experimental group sources were cultivated separately under inflammatory conditions. The cells from the two groups were cultured for osteogenic analysis. In addition, a specific antagonist of P2X7R, BBG was used to detect whether reversed the above process. At last, BBG was used to intervene in animal models of heterotopic ossification. Results Under inflammatory conditions, P2X7R expression of the Achilles tendon and osteogenic capability of SCs is higher in heterotopic ossification group (HOG) than in other two groups. The P2X7R expression was positive correlated with the capacity of osteogenesis of SCs. BBG can inhibit osteogenic differentiation and subsequent bone formation in the P2X7R overexpress of SCs. BBG impeded the heterotopic bone formation in animal model. Conclusions P2X7R is one of the crucial mediators in the formation of the HO, blocking which may represent a potential therapeutic target for HO.

scholarly journals Treatment of heterotopic ossification through remote ATP hydrolysis

2014 ◽  
Vol 6 (255) ◽  
pp. 255ra132-255ra132 ◽  
Author(s):  
Jonathan R. Peterson ◽  
Sara De La Rosa ◽  
Oluwatobi Eboda ◽  
Katherine E. Cilwa ◽  
Shailesh Agarwal ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Soft Tissues ◽  
Atp Hydrolysis ◽  
Burn Injury ◽  
In Vitro Assays ◽  
Osteogenic Potential ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation

Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein–mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3′,5′-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury–exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.

scholarly journals Synostosis Between Pubic Bones due to Neurogenic, Heterotopic Ossification

2006 ◽  
Vol 6 ◽  
pp. 2486-2490 ◽  
Author(s):  
Subramanian Vaidyanathan ◽  
Peter L. Hughes ◽  
Bakul M. Soni
Keyword(s):  
Bone Formation ◽  
Heterotopic Ossification ◽  
Foley Catheter ◽  
Symphysis Pubis ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Suprapubic Catheter ◽  
Suprapubic Cystostomy ◽  
Urine Leak ◽  
Irregular Margin

Neurogenic, heterotopic ossification is characterised by the formation of new, extraosseous (ectopic) bone in soft tissue in patients with neurological disorders. A 33-year-old female, who was born with spina bifida, paraplegia, and diastasis of symphysis pubis, had indwelling urethral catheter drainage and was using oxybutynin bladder instillations. She was prescribed diuretic for swelling of feet, which aggravated bypassing of catheter. Hence, suprapubic cystostomy was performed. Despite anticholinergic therapy, there was chronic urine leak around the suprapubic catheter and per urethra. Therefore, the urethra was mobilised and closed. After closure of the urethra, there was no urine leak from the urethra, but urine leak persisted around the suprapubic catheter. Cystogram confirmed the presence of a Foley balloon inside the bladder; there was no urinary fistula. The Foley balloon ruptured frequently, leading to extrusion of the Foley catheter. X-ray of abdomen showed heterotopic bone formation bridging the gap across diastasis of symphysis pubis. CT of pelvis revealed heterotopic bone lying in close proximity to the balloon of the Foley catheter; the sharp edge of heterotopic bone probably acted like a saw and led to frequent rupture of the balloon of the Foley catheter. Unique features of this case are: (1) temporal relationship of heterotopic bone formation to suprapubic cystostomy and chronic urine leak; (2) occurrence of heterotopic ossification in pubic region; (3) complications of heterotopic bone formation viz. frequent rupture of the balloon of the Foley catheter by the irregular margin of heterotopic bone and difficulty in insertion of suprapubic catheter because the heterotopic bone encroached on the suprapubic track; (4) synostosis between pubic bones as a result of heterotopic ossification..Common aetiological factors for neurogenic, heterotopic ossification, such as forceful manipulation, trauma, or spasticity, were absent in this patient. Since heterotopic bone formation was observed in the pubic region after suprapubic cystostomy and chronic urine leak, it is possible that risk factors related to the urinary tract might have played a role in heterotopic bone formation, which resulted in synostosis between pubic bones.

scholarly journals Circ-FURIN Expression Enhances Osteoblast Differentiation In Dental Pulp Stem Cells Via SOX11 Signaling Pathway Sponging miR-125

2021 ◽  
Author(s):  
Fang Ji ◽  
Yueting Lin ◽  
Jing Pan ◽  
Zhao Yang ◽  
Qianhui Ren ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Formation ◽  
Signaling Pathway ◽  
Dental Pulp ◽  
Osteoblast Differentiation ◽  
Dental Pulp Stem Cells ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Downstream Target ◽  
Report Analysis

Abstract Background: Many studies have found that circRNA plays a part in osteoblast differentiation. However, its mechanism remains unknown. Methods: High-throughput sequencing was used to identifield the different expression of circRNA during osteogenic dental pulp stem cells (DPSCs) differentiation. Luciferase report analysis and RT-qPCR were used to clarify the expression and regulation relationship among circ-FURIN, miR-125 and SOX11. The heterotopic bone formation experiment was further used to confirm the osteoblast differentiation of DPSC with different expression of circ-FURIN, miR-125 and SOX11. Results: Study indicated that circ-FURIN expression remarkably increased during osteoblast differentiation, yet circ-FURIN knockdown suppressed it. Bioinformatics and luciferase results discovered that miR-125 is the downstream target of circ-FURIN. Furthermore, circ-FURIN upregulation decreased miR-125 expression. MiR-125 upregulation restored the promotion effect of circ-FURIN on osteogenic DPSC differentiation. Luciferase report analysis verified that SOX11 is miR-125 downstream target. miR-125 overexpression suppressed osteogenic DPSC differentiation through targeting SOX11. SOX11 overexpression restored miR-125 inhibitory effect on osteogenic DPSC differentiation. In vivo experiments with heterotopic bone model suggested that circ-FURIN overexpression has crucial function to enhance heterotopic bone formation. Conclusions: In summary, circ-FURIN enhances osteoblast DPSC differentiation via the SOX11 signaling pathway by sponging miR-125. These findings suggest a novel therapeutic target for osteoporosis treatment.

scholarly journals Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dali Zhang ◽  
Junlan Huang ◽  
Xianding Sun ◽  
Hangang Chen ◽  
Shuo Huang ◽  
...  
Keyword(s):  
Bone Formation ◽  
Heterotopic Ossification ◽  
Growth Factor Receptor ◽  
Lineage Tracing ◽  
Conditional Knockout ◽  
Heterotopic Bone ◽  
Dependent Manner ◽  
Heterotopic Bone Formation ◽  
Inflammatory Microenvironment ◽  
Achilles Tenotomy

AbstractAcquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2+ cells promote acquired HO development. Lineage tracing studies reveal that Col2+ cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1+ LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2+ lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.

External Beam Radiation Helps Prevent Heterotopic Bone Formation in Patients With a History of Heterotopic Ossification

2006 ◽  
Vol 21 (5) ◽  
pp. 731-736 ◽  
Author(s):  
Samuel T. Chao ◽  
Shih-Yuan Lee ◽  
Lester S. Borden ◽  
Michael J. Joyce ◽  
Viktor E. Krebs ◽  
...  
Keyword(s):  
Bone Formation ◽  
Heterotopic Ossification ◽  
External Beam Radiation ◽  
Heterotopic Bone ◽  
External Beam ◽  
Heterotopic Bone Formation ◽  
Beam Radiation ◽  
History Of

scholarly journals Post-COVID-19 exacerbation of fibrodysplasia ossificans progressiva with multiple flare-ups and extensive heterotopic ossification in a 45-year-old female patient

2021 ◽  
Author(s):  
Lovorka Grgurevic ◽  
Rudjer Novak ◽  
Stela Hrkac ◽  
Grgur Salai ◽  
Simeon Grazio
Keyword(s):  
Heterotopic Ossification ◽  
Female Patient ◽  
Soft Tissues ◽  
Hereditary Disease ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Cytokine Analysis ◽  
Viral Illness ◽  
First Time

AbstractFibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.

scholarly journals Overexpression of bone morphogenetic protein 2 through aberrant canonical Wnt/β-catenin signaling pathway plays an important role in heterotopic ossification of adrenal myelolipoma

2014 ◽  
Vol 8 (1-2) ◽  
pp. 104 ◽  
Author(s):  
Yozo Mitsui ◽  
Hiroaki Yasumoto ◽  
Miho Hiraki ◽  
Naoko Arichi ◽  
Noriyoshi Ishikawa ◽  
...  
Keyword(s):  
Bone Formation ◽  
Heterotopic Ossification ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Bone Morphogenetic Protein 2 ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Adrenal Myelolipoma ◽  
Morphogenetic Protein ◽  
Canonical Wnt

The precise mechanism of heterotopic ossification caused by several types of tumours is largely unknown. However, recent studies have indicated that bone morphogenetic protein 2 (BMP2) is closely linked to the Wnt/β-catenin signaling pathway in this rare phenomenon of bone formation. We report a rare case of adrenal myelolipoma (ML) in a 27-year-old woman with heterotopic bone formation. Immunohistochemical findings showed BMP2 expression in the cytoplasm of tumour cells, as well as the matrix adjacent to newly developed bone tissue. In addition, β-catenin was prominent in the cytoplasm and nuclei of BMP2-positive tumour cells. To the best of our knowledge, this is the first report of adrenal ML showing heterotopic ossification with accelerated expression of both BMP2 and β-catenin. Our case findings indicate that BMP2 overexpression via aberrant canonical Wnt/β-catenin signaling may contribute to heterotopic bone formation occurring in adrenal ML.

scholarly journals Over-expression of wild-type ACVR1 in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification

2021 ◽  
Author(s):  
Masakazu Yamamoto ◽  
Sean J Stoessel ◽  
Shoko Yamamoto ◽  
David J Goldhamer
Keyword(s):  
Heterotopic Ossification ◽  
Cultured Cells ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Clinical Aspects ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Wild Type ◽  
Over Expression ◽  
Severity Of Injury ◽  
Perinatal Lethality

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally over-express human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 over-expression and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive over-expression of ACVR1 also provided protection from spontaneous HO, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 over-expression functions cell-autonomously by reducing osteogenic signaling in response to activin A. Manipulating the stoichiometry of FOP-causing and wild-type ACVR1 receptors may provide the foundation for novel therapeutic strategies to treat this devastating disease.

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