Animal models of temporomandibular joint heterotopic ossification: a scoping review.

There are few animal models for heterotopic ossification of the temporomandibular joint (TMJ-HO). This scoping review provides an overview of current knowledge on the induction methods and specific conditions required to produce TMJ-HO in various animal models. Two independent reviewers selected papers from the PubMed, Web of Science, and Cochrane Library databases. The inclusion criteria were articles in English, in vivo studies, and a TMJ-HO induction method. Observational, in vitro, human studies, reviews, and book chapters were excluded. Twenty-four publications were included. HO was surgically, genetically, or chemically induced through single or combined defects in the condyle, articular disc, and temporal bone in animal models (sheep=9 studies, mouse=5, rat=4, rabbit=2, pig=2, goat=1, dog=1, monkey=1) specific for traumatic TMJ-HO (n=4), ankylosis (n=9), osteoarthritis (n=8), experimental disc perforation (n=1), status post-TMJ replacement (n=1), and status post bilateral sagittal split osteotomy (n=1). TMJ-HO remains challenging to study due to its multifactorial etiology and largely unknown pathogenesis, which varies between species. There is a need for more accurate, reproducible animal models that can be extrapolated to human TMJ-HO and a consolidated clinical classification system to allow for meaningful future research.

Peripheral inflammatory T cell subsets are effective predictive factors in the development of heterotopic ossification after posttraumatic elbow surgery.

Heterotopic ossification refers to the pathological formation of extra-skeletal bone. It is a common complication of trauma or surgery that can cause disability and has no definitive cure. Furthermore, the mechanisms underlying chronic inflammation during ossification remain unclear. Therefore, this study aimed to elucidate the systemic immune microenvironment status of heterotopic ossification and identify biomarkers of therapeutic efficacy and recurrence. A combination of stereoarthrolysis with prophylactic radiotherapy and non-steroidal anti-inflammatory drugs was used to treat patients with heterotopic ossification. Changes were observed in peripheral blood lymphocyte levels after treatment. The number of IFNγ+CD8+T cells (3.753 % vs 12.90 %, P < 0.0001) and IL17+CD4+T cells (3.420 % vs 5.560 %, P = 0.0281) were was higher in the peripheral blood of relapsed patients with heterotopic ossification than in that of non-relapsed patients. Similarly, the number of these cells was elevated in patients who developed heterotopic ossification after posttraumatic elbow surgery. Peripheral CD8+T cells derived from patients with this pathology promoted osteogenesis through IFNγ expression in vitro. Our findings demonstrate that IFNγ+CD8+T cells and IL17+CD4+T cells are potential biomarkers of heterotopic ossification after posttraumatic elbow surgery. Furthermore, these cells can be used to predict therapeutic efficacy and relapse after combination therapy.

Heterotopic ossification of the elbow joint in a child: Successful surgical resection - A case report.

Background: This case report describes the occurrence of a rare heterotopic ossification of the elbow joint in a child, caused by inappropriate movement after trauma. A successful operation to remove heterotopic ossification was described in the report with satisfactory results. Case presentation: A 7-year-old boy suffered a supracondylar fracture of the humerus after an accidental fall, and after immobilization with a cast, improper movement resulted in heterotopic ossification of the elbow joint, which severely affected joint function. The heterotopic ossification was surgically removed and a complete recovery was demonstrated at 18 months follow-up. The heterotopic ossification was successfully removed with good elbow function and no recurrence at 18 months follow-up. Conclusions: The purpose of this report is to show the good results with surgical treatment of heterotopic ossification of the elbow joint in children,when conservative treatment does not work.

Endogenous hydrogen sulfide accelerated trauma-induced heterotopic ossification through the Ca2+/ERK pathway-enhanced aberrant osteogenic activity.

Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H2S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H2S accumulation within the tHO region. Increased production of endogenous H2S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H2S production or directly absorption of H2S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca2+/ERK pathway was the downstream molecular event of H2S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H2S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R-ZnO nanoparticles in both clearing of H2S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO.

Heterotopic ossification postsuperficial medial collateral ligament pie-crusting: a case report.

Anterior cruciate ligament and meniscus tears are common among sports injuries. There are different techniques for addressing anterior cruciate ligament and meniscus tears, with distinct indications, advantages, and disadvantages. We present the case of a 23-year-old male who underwent right anterior cruciate ligament reconstruction and posterior horn medial meniscus repair using an all-inside technique via superficial medial collateral ligament (sMCL) pie-crusting. Clinical examination and radiological investigations a few months later identified calcifications on the medial side of the right knee. We diagnosed the patient with heterotopic ossification post-sMCL pie-crusting; no apparent causal factors were present. To our knowledge, there have been no documented instances of heterotopic ossification following sMCL pie-crusting. In conclusion, heterotopic ossification may occur after sMCL pie-crusting; further studies are needed on this subject.

Comparative analysis of 'functional excision' of heterotopic ossification around the hip - computed tomography (CT) navigation guided versus conventional excision.

PURPOSE: We aim to analyse and compare the efficacy of the excision of HO around the hip with and without CT-guided navigation. We also aim to compare the functional outcome between CT navigation guided versus conventional excision of HO. PATIENTS AND METHODS: This study is a retrospective analysis of prospectively collected data from 2015 to 2022. There were 23 patients (24 hips) in the final cohort. Intraoperative CT navigation guided excision was performed in 7 hips and conventional excision of HO was done in 17 hips. The HO was classified by Brooker's grading in radiographs. CT scan was taken preoperatively in all patients to exactly identify the volume, location and preoperative planning. The functional outcome was analysed according to Harris Hip Score (HHS) and International Hip Outcome Tool (iHOT) for self-ambulatory patients and improvement in the sitting or nursing care was assessed in patients mobilising with wheelchair or walker support. Any complications or recurrence noted postoperatively and in follow-up were recorded. RESULTS: The mean follow-up was 41.2 months in the CT navigation-guided excision group and 55 months in the conventional excision group. According to Brooker's grading, grade IV was present in 20 hips and grade III in four hips. Twelve patients were self-ambulatory and the other 12 patients were requiring support for mobilisation. There was a significant improvement in the HHS from 21.3 ± 3.7, 18.3 ± 2.5 preoperatively to 75.2 ± 8.3, 72.2 ± 4.3 postoperatively in the CT navigation guided and conventional group respectively (p < 0.001) in the self-ambulatory group. There was one anterior wall and one partial posterior wall fracture in the conventional group. One patient in the conventional group had a deep infection and recurrence. One patient had a superficial infection and another had superficial vein thrombosis in the CT guided excision group. CONCLUSION: Intraoperative CT navigation helps to exactly localize the HO and facilitates safe excision. Functional excision of the HO leads to better nursing care and functional outcomes between both groups.

Research trends and hotspots of myositis ossificans: a bibliometric analysis from 1993 to 2022.

Myositis ossificans (MO) is characterized by benign heterotopic ossificans in soft tissues like muscles, which can be classified into nonhereditary MO and fibrodysplasia ossificans progressiva (FOP). Although MO has been studied for decades, no research reviewed and analyzed the features of publications in this field quantitatively and qualitatively. Using bibliometrics tools (bibliometrix R package, VOSviewer, and CiteSpace), we conducted a bibliometric analysis of 1280 articles regarding MO in the Web of Science Core Collection database from 1993 to 2022. The annual number of publications and related research areas in the MO field increased gradually in the past 20 years. The USA contributed the most percentage (42.58%) of articles. The University of Pennsylvania (UPenn) and the Journal Bone published the most articles among all institutions and journals. Kaplan FS and Shore EM from UPenn were the top two scholars who made the largest contributions to this field. Keyword analysis showed that research hotspots changed from traumatic MO and clinical management of MO to the genetic etiology, pathogenesis, and treatment of FOP. This study can provide new insights into the research trends of MO and helps researchers grasp and determine future study directions more easily.

Single-cell RNA sequencing uncovers cellular heterogeneity and the progression of heterotopic ossification of the elbow.

Heterotopic ossification of the elbow (HOE) is a complicated pathologic process characterized by extra bone formation in the elbow. Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells into osteoblasts. The aim of this study was to explore the cellular origin and progression of HOE by single-cell RNA sequencing. We identified 13 clusters of cells in HOE and further analyzed the subclusters for 4 of the main cell types. Six subclusters of osteoblasts, nine subclusters of chondrocytes, six subclusters of fibroblasts, and five subclusters of mononuclear phagocytes (MPs) were identified and analyzed. The new findings on osterix (OSX) and SOX9 expression in osteoblast subclusters and chondrocyte subclusters indicate that HOE is mediated through endochondral ossification. Further identification of the corresponding signature gene sets of distinct subclusters indicated that subclusters of osteoblasts_3, osteoblasts_4, osteoblasts_5, and osteoblasts_6 are relatively more mature during the osteoblastic progression of HOE. The trajectory analysis of the osteoblasts demonstrated that some genes were gradually downregulated, such as CRYAB, CCL3, SFRP4, WIF1, and IGFBP3, while other critical genes were upregulated, such as VCAN, IGFBP4, FSTL1, POSTN, MDK, THBS2, and ALPL, suggesting that these factors may participate in HOE progression. Cell-cell communication networks revealed extensive molecular interactions among the 13 HOE clusters. Ligand-receptor pairs for IL6, COL24A1, COL22A1, VWF, FZD6, FGF2, and NOTCH1 were identified, suggesting that multiple signaling pathways may be involved in HOE. In conclusion, this study provided the cellular atlas for HOE. We have established a greater extent of the heterogeneity of HOE cells than previously known through transcriptomic analysis at the single-cell level. We have observed gradual patterns of signature gene expression during the differentiation and maturation progression of osteoblasts from stem cells in HOE with higher resolution. The cell heterogeneity of HOE deserves further investigation to pave the way for identification of potential targets for HOE early diagnosis and therapeutic treatment.

Artificial intelligence in predicting postoperative heterotopic ossification following anterior cervical disc replacement.

OBJECTIVE: This study aimed to develop and validate a machine learning (ML) model to predict high-grade heterotopic ossification (HO) following Anterior cervical disc replacement (ACDR). METHODS: Retrospective review of prospectively collected data of patients undergoing ACDR or hybrid surgery (HS) at a quaternary referral medical center was performed. Patients diagnosed as C3-7 single- or multi-level cervical disc degeneration disease with > 2 years of follow-up and complete pre- and postoperative radiological imaging were included. An ML-based algorithm was developed to predict high grade HO based on perioperative demographic, clinical, and radiographic parameters. Furthermore, model performance was evaluated according to discrimination and overall performance. RESULTS: In total, 339 ACDR segments were included (61.65% female, mean age 45.65 ± 8.03 years). Over 45.65 ± 8.03 months of follow-up, 48 (14.16%) segments developed high grade HO. The model demonstrated good discrimination and overall performance according to precision (High grade HO: 0.71 ± 0.01, none-low grade HO: 0.85 ± 0.02), recall (High grade HO: 0.68 ± 0.03, none-low grade HO: 0.87 ± 0.01), F1-score (High grade HO: 0.69 ± 0.02, none-low grade HO: 0.86 ± 0.01), and AUC (0.78 ± 0.08), with lower prosthesis­endplate depth ratio, higher height change, male, and lower postoperative-shell ROM identified as the most important predictive features. CONCLUSION: Through an ML approach, the model identified risk factors and predicted development of high grade HO following ACDR with good discrimination and overall performance. By addressing the shortcomings of traditional statistics and adopting a new logical approach, ML techniques can support discovery, clinical decision-making, and intraoperative techniques better.

A scoping review on active vs. passive range of motion approaches to treat heterotopic ossification at the elbow.

Objective: The objective of this scoping review is to synthesize and clarify literature on the effectiveness of active and passive range of motion therapy techniques to address range of motion in people with heterotopic ossification (HO), and to provide guidance to therapists in clinical decision-making based on current evidence. Method: To find articles that included therapeutic interventions to maintain or improve range of motion in people with heterotopic ossification, the authors searched the following databases: Cochrane Database of Systematic Reviews, PubMed, CINAHL, PsychINFO, Web of Science, and OTSeeker. To ensure that the search was comprehensive, the authors also searched Burns and Trauma, Burns Journal, Burns Open, and the Journal of Hand Therapy. Searches were limited to peer-reviewed articles published in the English language. No publication date limits were set. The Physiotherapy Evidence Database PEDro scale was utilized to measure the validity of the methodological quality of each article. Results: Five studies met the inclusion criteria.. Two studies emphasized that passive range of motion was effective in less than 50% of their subjects, while the other three studies utilized active range of motion only, reporting 50% of patients did not require surgery. Discussion/conclusion: There is insufficient evidence to determine effective therapeutic management of HO and the literature that does exist is contradictory and inconclusive. Future research is necessary to determine if any effectiveness of manual therapeutic approaches exists for patients with HO.

A Novel Surgical Technique for the Management of Large-Volume Neurogenic Heterotopic Ossification Following a Spinal Cord Injury: The Sashimi Technique.

This case series investigates the efficacy of the "sashimi technique," a novel surgical approach utilizing a curved chisel for the resection of heterotopic ossification (HO). The main focus is on reducing resection margins and preventing excessive bone removal while maintaining optimal functional outcomes and preventing recurrence. Two cases illustrate successful outcomes in patients with spinal cord injuries and severe HO of the hip, emphasizing the precision of using the curved chisel-based technique in improving patient mobility while still achieving a desired resection margin. The study highlights the effectiveness of using a curved chisel in protecting neurovascular structures and maintaining resection precision. Additionally, the integration of postoperative radiotherapy and pharmacological treatment is emphasized as a strategy to prevent recurrence. The goal of this procedure is to improve functional outcomes and patient quality of life.

Post-Traumatic Radio-ulnar Synostosis Managed by the Excision of the Bone Bridge and Palmaris Longus Encircling Loop over the Ulna: A Case Report.

Introduction: Radioulnar synostosis is an uncommon complication of forearm fractures and presents with varying degrees of restricted forearm movement. The diaphysial distal third synostosis is less common and excision of the synostosis is fraught with risk of re-ossification. Use of inert or biological interposing material has thus been accompanied with the synostosis excision and various methods have been described. There is still no consensus on the ideal treatment method. Case Report: We, hereby, report a case of a long-standing radioulnar synostosis with rotational restriction of movement. Despite the movement restriction, the patient could perform basic activities of daily living and wanted to improve the movements. The presence of diaphyseal radioulnar synostosis was conformed on the radiographs and computerized tomography scan. A volar forearm approach was used and the bony bridge was excised. The ipsilateral native palmaris longus (PL) tendon was extracted from distal wrist crease and with its proximal attachment intact, circumferentially wrapped around the ulnar raw surface as an interposing material. Apart from this, free fat was also placed at the synostosis site. In the long-term follow-up of 10 years, there was no radiological evidence of re-ossification noted. The clinical improvement was not much but the patient was performing activities of daily living with no discomfort. Conclusion: The use of an encircling loop of the native PL tendon, over the raw surface of one of the forearm bones, may be another useful method to decrease the chances of recurrence following the excision of the synostosis.

Delayed femoral artery injury caused by heterotopic ossification: a rare case report and review of the literature.

BACKGROUND: Arterial injury caused by heterotopic ossification (HO) following fractures is rarely reported, yet it can have catastrophic consequences. This case report presents a unique instance of femoral artery injury and hematoma organization, occurring a decade after intramedullary nail fixation for a femoral shaft fracture complicated by HO. CASE PRESENTATION: A 56-year-old male presented with right femoral artery injury and organized hematoma, a decade after suffering bilateral femoral shaft fractures with mild head injury in a traffic accident. He had received intramedullary nailing for the right femoral shaft fracture and plate fixation for the left side in a local hospital. Physical examination revealed two firm, palpable masses with clear boundaries, limited mobility, and no tenderness. Peripheral arterial pulses were intact. Radiography demonstrated satisfactory fracture healing, while a continuous high-density shadow was evident along the inner and posterior aspect of the right thigh. Computed tomography angiography identified a large mixed-density mass (16.8 × 14.8 × 20.7 cm) on the right thigh's medial side, featuring central calcification and multiple internal calcifications. The right deep femoral artery coursed within this mass, with a smaller lesion noted on the posterior thigh. Surgical consultation with a vascular surgeon led to planned intervention. The smaller mass was completely excised, but the larger one partially, as it encased the femoral artery. The inability to remove all HO was due to excessive bleeding. Postoperatively, the patient experienced no complications, and one-year follow-up revealed a favorable recovery with restoration of full right lower limb mobility. CONCLUSION: This case underscores the potential gravity of vascular injury associated with heterotopic ossification. Surgeons should remain vigilant regarding the risk of vascular injury during HO excision.

Disturbed glycolipid metabolism activates CXCL13-CXCR5 axis in senescent TSCs to promote heterotopic ossification.

Heterotopic ossification (HO) occurs as a common complication after injury, while its risk factor and mechanism remain unclear, which restricts the development of pharmacological treatment. Clinical research suggests that diabetes mellitus (DM) patients are prone to developing HO in the tendon, but solid evidence and mechanical research are still needed. Here, we combined the clinical samples and the DM mice model to identify that disordered glycolipid metabolism aggravates the senescence of tendon-derived stem cells (TSCs) and promotes osteogenic differentiation. Then, combining the RNA-seq results of the aging tendon, we detected the abnormally activated autocrine CXCL13-CXCR5 axis in TSCs cultured in a high fat, high glucose (HFHG) environment and also in the aged tendon. Genetic inhibition of CXCL13 successfully alleviated HO formation in DM mice, providing a potential therapeutic target for suppressing HO formation in DM patients after trauma or surgery.

AMPK induces PIAS3 mediated SUMOylation of E3 ubiquitin ligase Smurf1 impairing osteogenic differentiation and traumatic heterotopic ossification.

AMP-activated protein kinase (AMPK) is a typical sensor of intracellular energy metabolism. Our previous study revealed the role of activated AMPK in the suppression of osteogenic differentiation and traumatic heterotopic ossification, but the underlying mechanism remains poorly understood. The E3 ubiquitin ligase Smurf1 is a crucial regulator of osteogenic differentiation and bone formation. We report here that Smurf1 is primarily SUMOylated at a C-terminal lysine residue (K324), which enhances its activity, facilitating ALK2 proteolysis and subsequent bone morphogenetic protein (BMP) signaling pathway inhibition. Furthermore, SUMOylation of the SUMO E3 ligase PIAS3 and Smurf1 SUMOylation was suppressed during the osteogenic differentiation and traumatic heterotopic ossification. More importantly, we found that AMPK activation enhances the SUMOylation of Smurf1, which is mediated by PIAS3 and increases the association between PIAS3 and AMPK. Overall, our study revealed that Smurf1 can be SUMOylated by PIAS3, Furthermore, Smurf1 SUMOylation mediates osteogenic differentiation and traumatic heterotopic ossification through suppression of the BMP signaling pathway. This study revealed that promotion of Smurf1 SUMOylation by AMPK activation may be implicated in traumatic heterotopic ossification treatment.

Ossification of the posterior longitudinal ligament is linked to heterotopic ossification of the ankle/foot tendons.

INTRODUCTION: Systemic osteogenesis has been speculated to be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL). Our purpose was to compare the radiologic prevalence and severity of heterotopic ossification in foot tendons of Japanese patients with OPLL and to determine their association with systemic heterotopic ossification. MATERIALS AND METHODS: Clinical and radiographic data of 114 patients with OPLL were collected from 2020 to 2022. Control data were extracted from a medical database of 362 patients with ankle radiographs. Achilles and plantar tendon ossification were classified as grades 0-4, and the presence of osteophytes at five sites in the foot/ankle joint was assessed by radiography. Factors associated with the presence and severity of each ossification were evaluated by multivariable logistic regression and linear regression analysis. RESULTS: The prevalence of Achilles and plantar tendon ossification (grade ≥ 2) was 4.0-5.5 times higher in patients with OPLL (40-56%) than in the controls (10-11%). The presence of Achilles tendon ossification was associated with OPLL, age, and coexisting plantar tendon ossification, and was most strongly associated with OPLL (standardized regression coefficient, 0.79; 95% confidence interval, 1.34-2.38). The severity of Achilles and plantar tendon ossification was associated with the severity of ossification of the entire spinal ligament. CONCLUSIONS: The strong association of foot tendon ossification with OPLL suggests that patients with OPLL have a systemic osteogenesis background. These findings will provide a basis for exploring new treatment strategies for OPLL, including control of metabolic abnormalities.

Development and validation of a nomogram for predicting heterotopic ossification following spinal cord injury.

OBJECTIVE: Heterotopic ossification (HO) following spinal cord injury (SCI) can severely compromise patient mobility and quality of life. Precise identification of SCI patients at an elevated risk for HO is crucial for implementing early clinical interventions. While the literature presents diverse correlations between HO onset and purported risk factors, the development of a predictive model to quantify these risks is likely to bolster preventive approaches. This study is designed to develop and validate a nomogram-based predictive model that estimates the likelihood of HO in SCI patients, utilizing recognized risk factors to expedite clinical decision-making processes. METHODS: We recruited a total of 145 patients with SCI and presenting with HO who were hospitalized at the China Rehabilitation Research Center, Beijing Boai Hospital, from June 2016 to December 2022. Additionally, 337 patients with SCI without HO were included as controls. Comprehensive data were collected for all study participants, and subsequently, the dataset was randomly partitioned into training and validation groups. Using Least Absolute Shrinkage and Selection Operator regression, variables were meticulously screened during the pretreatment phase to formulate the predictive model. The efficacy of the model was then assessed using metrics including receiver-operating characteristic (ROC) analysis, calibration assessment, and decision curve analysis. RESULTS: The final prediction model incorporated age, sex, complete spinal cord injury status, spasm occurrence, and presence of deep vein thrombosis (DVT). Notably, the model exhibited commendable performance in both the training and validation groups, as evidenced by areas under the ROC curve (AUCs) of 0.756 and 0.738, respectively. These values surpassed the AUCs obtained for single variables, namely age (0.636), sex (0.589), complete spinal cord injury (0.681), spasm occurrence (0.563), and DVT presence (0.590). Furthermore, the calibration curve illustrated a congruence between the predicted and actual outcomes, indicating the high accuracy of the model. The decision curve analysis indicated substantial net benefits associated with the application of the model, thereby underscoring its practical utility. CONCLUSIONS: HO following SCI correlates with several identifiable risk factors, including male gender, youthful age, complete SCI, spasm occurrence and DVT. Our predictive model effectively estimates the likelihood of HO development by leveraging these factors, assisting physicians in identifying patients at high risk. Subsequently, correct positioning to prevent spasm-related deformities and educating healthcare providers on safe lower limb mobilization techniques are crucial to minimize muscle injury risks from rapid iliopsoas muscle extension. Additionally, the importance of early DVT prevention through routine screening and anticoagulation is emphasized to further reduce the incidence of HO.

Angiogenesis in heterotopic ossification: From mechanisms to clinical significance.

Heterotopic ossification (HO) refers to the formation of pathologic bone in nonskeletal tissues (including muscles, tendons or other soft tissues). HO typically occurs after a severe injury and can occur in any part of the body. HO lesions are highly vascularized. Angiogenesis, which is the formation of new blood vessels, plays an important role in the pathophysiology of HO. Surgical resection is considered an effective treatment for HO. However, it is difficult to completely remove new vessels, which can lead to the recurrence of HO and is often accompanied by significant problems such as intraoperative hemorrhage, demonstrating the important role of angiogenesis in HO. Here, we broadly summarize the current understanding of how angiogenesis contributes to HO; in particular, we focus on new insights into the cellular and signaling mechanisms underlying HO angiogenesis. We also review the development and current challenges associated with antiangiogenic therapy for HO.

Personalizing Prophylactic Radiotherapy for Hip Heterotopic Ossification: An AMSTAR-2 Compliant Review of Meta-analyses.

BACKGROUND/AIM: Heterotopic ossification (HO) is a common complication following total hip arthroplasty. Various prophylactic treatments have been proposed, including radiotherapy (RT). This review summarizes the evidence from meta-analyses on the efficacy of RT in preventing hip HO. MATERIALS AND METHODS: A literature search was conducted on PubMed. The quality of the meta-analyses was assessed using the AMSTAR-2 tool. RESULTS: Seven meta-analyses were included. One meta-analysis reported a significant reduction in HO occurrence after RT compared to the control group. Comparing RT and non-steroidal anti-inflammatory drugs, one and two meta-analyses showed significantly greater efficacy of RT in preventing severe HO and better outcomes in patients receiving drugs, respectively. Regarding RT settings, the postoperative and preoperative RT were each supported by one meta-analysis. Furthermore, two meta-analyses showed an advantage of multi-fractionated RT over single fraction RT. The overall confidence rate of the meta-analyses was moderate, low, and critically low in one, three, and three meta-analyses, respectively. CONCLUSION: RT is a confirmed prophylactic intervention for HO. However, the precise optimization of timing, dosage, and fractionation requires elucidation. Future research should focus on the development of predictive models through large-scale data collection and advanced analytics to refine individualized treatment strategies and assess RT comparative effectiveness with drugs.

Suppression of TNF-α activity by immobilization rescues Mkx expression and attenuates tendon ossification in a mouse Achilles tenotomy model.

Traumatic heterotopic ossification is a condition in which extraskeletal bone formation occurs in soft tissues after injury. It most commonly occurs in patients who had major orthopedic surgery and in those with severe extremity injuries. The lesion causes local pain and can impair motor function of the affected limb, but there is currently no established prophylaxis or treatment for this condition. In this study, we show that immobilization at an early stage of the inflammatory response after injury can attenuate ossification formation in a murine Achilles tenotomy model. Gene expression analysis revealed a decrease in the expression of Tnf and an increase in the expression of Mkx, which encodes one of the master regulators of tendon differentiation, Mohawk. Notably, we found that TNF-α suppressed the expression of Mkx transcripts and accelerated the osteogenic differentiation of tendon-derived mesenchymal stem cells (MSCs), suggesting that TNF-α acts as a negative regulator of Mkx transcription. Consistent with these findings, pharmaceutical inhibition of TNF-α increased the expression of Mkx transcripts and suppressed bone formation in this mouse model. These findings reveal the previously unrecognized involvement of TNF-α in regulating tendon MSC fate through suppression of Mkx expression and suggest that TNF-α is a potential target for preventing traumatic heterotopic ossification.