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Synergistic inhibition of endochondral bone formation by silencing Hif1? and Runx2 in trauma-induced heterotopic ossification.

ABSTRACT: Angiogenesis and osteogenesis are tightly coupled during bone development. We studied the effect of inhibition of Hif1? and Runt-related protein 2 (Runx2) on the formation of heterotopic ossification (HO). We constructed lentivirus vectors expressing Hif1? small interfering RNA (siRNA) and Runx2 siRNA. The inhibition of Hif1? function impaired osteoblast proliferation while osteoblasts differentiated normally. Osteoblasts lacking Runx2 proliferated normally while the differentiation was impaired. The osteoblast differentiation was significantly inhibited by co-Runx2 and Hif1? siRNA treatment. The formation of HO by inhibiting Runx2 and Hif1? in an animal model induced by Achilles tenotomy was investigated. The results showed that lacking of Runx2 and Hif1? could inhibit HO formation. Inhibition of Hif1? prevented HO formation only at the initial step and inhibition of Runx2 worked both at the initial step and after chondrogenesis. Angiogenesis and the expressions of osteogenic genes were downregulated in the Hif1? siRNA group. We found synergistic inhibition of endochondral bone formation by silencing Hif1? and Runx2. Our study provided new insight into the roles of Hif1? and Runx2 during the processes of endochondral bone formation, and had important implications for the new therapeutic methods to inhibit HO or to enhance bone formation.

SUBMITTER: Lin L

PROVIDER: S-EPMC3149159 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Synergistic inhibition of endochondral bone formation by silencing Hif1α and Runx2 in trauma-induced heterotopic ossification.

Lin Lin L Shen Qi Q Leng Huijie H Duan Xiaoning X Fu Xin X Yu Changlong C

Molecular therapy : the journal of the American Society of Gene Therapy 20110531 8

Angiogenesis and osteogenesis are tightly coupled during bone development. We studied the effect of inhibition of Hif1α and Runt-related protein 2 (Runx2) on the formation of heterotopic ossification (HO). We constructed lentivirus vectors expressing Hif1α small interfering RNA (siRNA) and Runx2 siRNA. The inhibition of Hif1α function impaired osteoblast proliferation while osteoblasts differentiated normally. Osteoblasts lacking Runx2 proliferated normally while the differentiation was impaired ...[more]

PMID: 21629226

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Project description:ObjectiveTo demonstrate the pro-osteogenic effect of burn injury on heterotopic bone formation using a novel burn ossicle in vivo model.BackgroundHeterotopic ossification (HO), or the abnormal formation of bone in soft tissue, is a troubling sequela of burn and trauma injuries. The exact mechanism by which burn injury influences bone formation is unknown. The aim of this study was to develop a mouse model to study the effect of burn injury on heterotopic bone formation. We hypothesized that burn injury would enhance early vascularization and subsequent bone formation of subcutaneously implanted mesenchymal stem cells.MethodsMouse adipose-derived stem cells were harvested from C57/BL6 mice, transfected with a BMP-2 adenovirus, seeded on collagen scaffolds (ossicles), and implanted subcutaneously in the flank region of 8 adult mice. Burn and sham groups were created with exposure of 30% surface area on the dorsum to 60°C water or 30°C water for 18 seconds, respectively (n = 4/group). Heterotopic bone volume was analyzed in vivo by micro-computed tomography for 3 months. Histological analysis of vasculogenesis was performed with platelet endothelial cell adhesion molecule staining. Osteogenic histological analysis was performed by Safranin O, Picrosirius red, and aniline blue staining. Qualitative analysis of heterotopic bone composition was completed with ex vivo Raman spectroscopy.ResultsSubcutaneously implanted ossicles formed heterotopic bone. Ossicles from mice with burn injuries developed significantly more bone than sham control mice, analyzed by micro-computed tomography at 1, 2, and 3 months (P < 0.05), and had enhanced early and late endochondral ossification as demonstrated by Safranin O, Picrosirius red, and aniline blue staining. In addition, burn injury enhanced vascularization of the ossicles (P < 0.05). All ossicles demonstrated chemical composition characteristic of bone as demonstrated by Raman spectroscopy.ConclusionsBurn injury increases the predilection to osteogenic differentiation of ectopically implanted ossicles. Early differences in vascularity correlated with later bone development. Understanding the role of burn injury on heterotopic bone formation is an important first step toward the development of treatment strategies aimed to prevent unwanted and detrimental heterotopic bone formation.

Project description:Heterotopic Ossification (HO) is a potential long-term complication in orthopaedic surgery. It is commonly classified according to the Brooker classification, which is based on radiological findings. To our knowledge the correlation of histological features to the Brooker grade is unknown as is the association between HO and the indication for revision. The aim of this paper is to analyze the ossification grade of HO tissue in patients undergoing revision hip and knee arthroplasty and to propose a histologically based classification system for HO. We also assess the relationship between the grade of HO and the indication for revision (septic and aseptic revision). From January to May 2019 we collected 50 human HO samples from hip and knee revision arthroplasty cases. These tissue samples were double-blinded and sent for histopathological diagnostic. Based on these results, we developed a classification system for the progression of HO. The grade of ossification was based on three characteristics: Grade of heterotopic ossification (Grade 1-3), presence of necrosis (N0 or N1) and the presence of osteomyelitis (HOES-Score Type 1 to 5). Demographic data as well as surgical details and indication for surgery was prospectively collected from clinical records. Fifty tissue samples were harvested from 44 hips and 6 knee joints. Of these 33 exhibited Grade I ossifications (66%), followed by 11 Grade II (22%) and one Grade III (2%). Necrosis was noted in two tissue samples (4%) and 2 more had osteomyelitis findings according to HOES-Score. Six samples (12%) with radiologically suggestive of HO turned out to be wear-induced synovitis, SLIM Type 1. Of these cases 16 were septic (32%) and 34 aseptic (68%) revisions. Most of the HO tissue samples were classified as a low-grade. High-grade ossification-Score is rare. Higher grades of ossification seem to be associated with septic revision cases. Wear-induced synovitis potentially influences HO development. A histological scoring system for ossification grading can be derived from the data presented in this study.

Dataset Information

Synergistic inhibition of endochondral bone formation by silencing Hif1? and Runx2 in trauma-induced heterotopic ossification.

Publications

Synergistic inhibition of endochondral bone formation by silencing Hif1α and Runx2 in trauma-induced heterotopic ossification.

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