Animal Models of Typical Heterotopic Ossification

Kan, Lixin; Kessler, John A.

doi:10.1155/2011/309287

Cited by 59 publications

(76 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The hallmark of this process is BMP activity; it is known and accepted that BMP-2 is the prototypical molecule for osteogenesis [50]. Terminal osteogenic differentiation is promoted by rhBMP-2; thus, abrogating BMP-induced differentiation has a robust biological basis for HO prophylaxis [32,42].…”

Section: Discussionmentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

Background Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. Questions/purposes We hypothesized that (1) nanogelmediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. Methods Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImage TM assay). Results Gene expression assays demonstrated that nanogelbased RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% ± 19.53% (p \ 0.001) and 43.22% ± 18.01% (both p \ 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% ± 10.85% and 47.65% ± 9.80% (both p \ 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% ± 12.0% and 33.6% ± 13.8% (both p \ 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% ± 14.0% and 47.7% ± 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that Two of the authors (ARS, EH) contributed equally.

show abstract

Section: Discussionmentioning

confidence: 99%

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Shrivats

Hsu

Averick

et al. 2015

Clinical Orthopaedics &Amp; Related Research

View full text Add to dashboard Cite

show abstract

“…Tissue formed through the process of HO is intriguing since it is composed of endochondral bone, which contains a central canal filled with bone marrow [1]. This distinguishes the process of HO from other pathological conditions characterised by the deposition of ectopic mineral within soft tissues, such as progressive osseous heteroplasia (lacks endochondral ossification) and dystrophic calcification (associated with the development of kidney stones and lacking the presence of bone marrow) [2,3].…”

Section: Heterotopic Ossificationmentioning

confidence: 99%

“…However, despite continued efforts to identify the cellular and molecular events leading to HO, the mechanisms of pathogenesis continue to remain elusive. To date many contributory biological factors have been implicated in the etiology (see diagram 1), including the bone morphogenetic proteins (BMPs), inflammation, prostaglandin E2, hypercalcemia, hypoxia, abnormal nerve activity, immobilization and dysregulation of hormones [1,24]. However, in addition to the biological contribution, HO is also associated with a change in local biomechanics, as can be observed following reparative surgeries, such as cervical total disc replacement, where resulting changes in height of the functional segmental unit or increases in range of motion may influence the formation of HO [25].…”

Section: Pathogenesismentioning

confidence: 99%

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

et al. 2015

View full text Add to dashboard Cite

“…[4,5] New approaches to develop bone-like materials are also required for the augmentation of bone defects and ultimately the replacement and surgical transplantation of tissue grafts. [1,[19][20][21] In this context, the present work focused on developing a new, biological model of bone tissue formation, which would allow long term, whole construct testing of potential therapeutic drugs or of anabolic factors in a less complex environment. The aim was to develop a system that could in future be easily manipulated biochemically and biomechanically to simulate the ossification microenvironment encountered in both normal and pathological environments and that could ultimately be applied to investigate both biological and physical research questions.…”

Section: Introductionmentioning

confidence: 99%

An In Vitro Model for the Development of Mature Bone Containing an Osteocyte Network

et al. 2017

View full text Add to dashboard Cite

Bone is a dynamic tissue that remodels continuously in response to local mechanical and chemical stimuli. This process can also result in maladaptive ectopic bone in response to injury, yet pathological differences at the molecular and structural levels are poorly understood. A number of in vivo models exist but can often be too complex to allow isolation of factors which may stimulate disease progression. A self‐structuring model of bone formation is presented using a fibrin gel cast between two calcium phosphate ceramic anchors. Femoral periosteal cells, seeded into these structures, deposit an ordered matrix that closely resembles mature bone in terms of chemistry (collagen:mineral ratio) and structure, which is adapted over a period of one year in culture. Raman spectroscopy and X‐ray diffraction confirm that the mineral is hydroxyapatite associated with collagen. Second‐harmonic imaging demonstrates that collagen is organized similarly to mature mouse femora. Remarkably, cells differentiated to the osteocyte phase are linked by canaliculi (as demonstrated with nano‐computed tomography) and remained viable over the full year of culture. It is demonstrated that novel drugs can prevent ossification in constructs. This model can be employed to study bone formation in an effort to encourage or prevent ossification in a range of pathologies.

show abstract

Animal Models of Typical Heterotopic Ossification

Cited by 59 publications

References 82 publications

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification

An In Vitro Model for the Development of Mature Bone Containing an Osteocyte Network

Contact Info

Product

Resources

About