Antitumor necrotic factor agent promotes BMP-2-induced ectopic bone formation

Eguchi, Yoshitaka; Wakitani, Shigeyuki; Imai, Yuuki; Naka, Yoshifumi; Hashimoto, Yusuke; Nakamura, Hiroaki; Takaoka, Kunio

doi:10.1007/s00774-009-0127-x

Cited by 23 publications

(20 citation statements)

References 36 publications

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“…An accepted paradigm of HO formation includes three key components: multipotent progenitor cells capable of forming bone, a permissive niche, and an inciting inflammatory incident [6][7][8]. The majority of current literature supports a role for MSCs in modulating HO [9][10][11][12]. This is further confirmed by the fact that we observe trauma-induced HO to occur through an endochondral ossification process.…”

Section: Introductionsupporting

confidence: 70%

Effects of Aging on Osteogenic Response and Heterotopic Ossification Following Burn Injury in Mice

Peterson

Oluwatobi

Brownley

et al. 2015

Stem Cells and Development

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Heterotopic ossification (HO) is a common and debilitating complication of burns, traumatic brain injuries, and musculoskeletal trauma and surgery. Although the exact mechanism of ectopic bone formation is unknown, mesenchymal stem cells (MSCs) capable of osteogenic differentiation are known to play an essential role. Interestingly, the prevalence of HO in the elderly population is low despite the high overall occurrence of musculoskeletal injury and orthopedic procedures. We hypothesized that a lower osteogenicity of MSCs would be associated with blunted HO formation in old compared with young mice. In vitro osteogenic differentiation of adipose-derived MSCs from old (18-20 months) and young (6-8 weeks) C57/BL6 mice was assessed, with or without preceding burn injury. In vivo studies were then performed using an Achilles tenotomy with concurrent burn injury HO model. HO formation was quantified using mCT scans, Raman spectroscopy, and histology. MSCs from young mice had more in vitro bone formation, upregulation of bone formation pathways, and higher activation of Smad and nuclear factor kappa B (NF-kB) signaling following burn injury. This effect was absent or blunted in cells from old mice. In young mice, burn injury significantly increased HO formation, NF-kB activation, and osteoclast activity at the tenotomy site. This blunted, reactive osteogenic response in old mice follows trends seen clinically and may be related to differences in the ability to mount acute inflammatory responses. This unique characterization of HO and MSC osteogenic differentiation following inflammatory insult establishes differences between age populations and suggests potential pathways that could be targeted in the future with therapeutics.

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Section: Introductionsupporting

confidence: 70%

Effects of Aging on Osteogenic Response and Heterotopic Ossification Following Burn Injury in Mice

Peterson

Oluwatobi

Brownley

et al. 2015

Stem Cells and Development

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“…It has been reported that TNF-α impaired BMP-2-induced ectopic bone formation in mice, and treatment with anti-TNF-α agents maintained bone mass and protected against bone loss caused by TNF-α [13]. To demonstrate the relationship between PGRN and TNF-α in BMP-2 mediated bone formation, an ectopic bone formation model was created in the calf muscle of WT and human TNF-α transgenic (TNF-Tg) mice.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that overexpression of TNF-α enhances bone resorption and inhibits osteogenesis induced by BMP-2 [13]. TNFR1 is known to mediate inflammatory function of TNF-α, which also induces inflammatory bone resorption [14].…”

Section: Introductionmentioning

confidence: 99%

The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling

Zhao¹,

Tian²,

Frenkel³

et al. 2013

Biomaterials

100

124

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Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-α signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-α-induced inflammatory osteoclastogenesis and protected BMP-2 mediated ectopic bone formation in TNFα transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-α signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions.

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“…The burst release of growth factors is, additionally, considered unfavorable from the point of view of optimal bone regeneration, as their controlled and prolonged release is of vital importance to make the material osteoinductive 182,183 . Also, tumorigenesis, ectopic expression and other forms of ill-directed growth resulting from the uncontrolled dosage or location of delivered BMPs and other growth factors, including platelet-derived growth factor-BB, and present serious potential problems pertaining to their usage 184,185,186,187 . Strictly speaking, with the healing process following injury that the implantation of a hard tissue substitute is consisting of multiple steps, including clotting, angiogenesis, inflammation, scar formation, etc., each one of which occurs at a narrowly defined time scale, it makes sense that regulatory molecules targeting these specific events should be released within similarly narrowly defined time windows.…”

Section: Additional Common Ingredients Of Composite Biomaterialsmentioning

confidence: 99%

When 1 + 1 > 2: Nanostructured composites for hard tissue engineering applications

Uskoković

2015

Materials Science and Engineering: C

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Multicomponent, synergistic and multifunctional nanostructures have taken over the spotlight in the realm of biomedical nanotechnologies. The most prospective materials for bone regeneration today are almost exclusively composites comprising two or more components that compensate for the shortcomings of each one of them alone. This is quite natural in view of the fact that all hard tissues in the human body, except perhaps the tooth enamel, are composite nanostructures. This review article highlights some of the most prospective breakthroughs made in this research direction, with the hard tissues in main focus being those comprising bone, tooth cementum, dentin and enamel. The major obstacles to creating collagen/apatite composites modeled after the structure of bone are mentioned, including the immunogenicity of xenogeneic collagen and continuously failing attempts to replicate the biomineralization process in vitro. Composites comprising a polymeric component and calcium phosphate are discussed in light of their ability to emulate the soft/hard composite structure of bone. Hard tissue engineering composites created using hard material components other than calcium phosphates, including silica, metals and several types of nanotubes, are also discoursed on, alongside additional components deliverable using these materials, such as cells, growth factors, peptides, antibiotics, antiresorptive and anabolic agents, pharmacokinetic conjugates and various cell-specific targeting moieties. It is concluded that a variety of hard tissue structures in the body necessitates a similar variety of biomaterials for their regeneration. The ongoing development of nanocomposites for bone restoration will result in smart, theranostic materials, capable of acting therapeutically in direct feedback with the outcome of in situ disease monitoring at the cellular and subcellular scales. Progress in this research direction is expected to take us to the next generation of biomaterials, designed with the purpose of fulfilling Daedalus’ dream - not restoring the tissues, but rather augmenting them.

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Antitumor necrotic factor agent promotes BMP-2-induced ectopic bone formation

Cited by 23 publications

References 36 publications

Effects of Aging on Osteogenic Response and Heterotopic Ossification Following Burn Injury in Mice

Effects of Aging on Osteogenic Response and Heterotopic Ossification Following Burn Injury in Mice

The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling

When 1 + 1 > 2: Nanostructured composites for hard tissue engineering applications

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