Loss of Smad3 gives rise to poor soft callus formation and accelerates early fracture healing

Kawakatsu, Motohisa; Kanno, Seiji; Gui, Ting; Gai, Zhibo; Itoh, Shousaku; Tanishima, Hiroyuki; Oikawa, Kosuke; Muragaki, Yasuteru

doi:10.1016/j.yexmp.2010.10.011

Cited by 18 publications

(10 citation statements)

References 35 publications

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“…On the other hand, the modification of the growth factors and cytokines content in the fracture haematoma has also been investigated. More specifically, IL-1β, IL-6, TNF, BMPs, TGF, PDGF, and VEGF modifications within the fracture site have been explored (Critchlow, Bland, & Ashhurst, 1995;Glass et al, 2011;Hollinger et al, 2008;Kawakatsu et al, 2011;Lange et al, 2010;Li et al, 2009;Nash et al, 1994;Pountos et al, 2014;Rozen et al, 2007;J. Street et al, 2002;Tarkka, 2003;Wallace, Cooney, Englund, & Lubahn, 2011).…”

Section: Discussionmentioning

confidence: 99%

The cytokines and micro‐environment of fracture haematoma: Current evidence

Walters

Pountos

Giannoudis

2017

J Tissue Eng Regen Med

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Fracture haematoma formation is the first and foremost important stage of fracture healing. It orchestrates the inflammatory and cellular processes leading to the formation of callus and the restoration of the continuity of the bone. Evidence suggests that blocking this initial stage could lead to an impairment of the overall bone healing process. This review aims to analyse the existing evidence of molecular contributions to bone healing within fracture haematoma and to determine the potential to modify the molecular response to fracture in the haematoma with the aim of improving union times. A comprehensive search of literature documenting fracture haematoma cytokine content was performed. Suitable papers according to prespecified criteria were identified and analysed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 89 manuscripts formed the basis of this analysis. Low oxygen tension, high acidity, and high calcium characterised initially the fracture haematoma micro-environment. In addition, a number of cytokines have been measured with concentrations significantly higher than those found in peripheral circulation. Growth factors have also been isolated, with an observed increase in bone morphogenetic proteins, platelet-derived growth factor, and transforming growth factor. Although molecular modification of fracture haematoma has been attempted, more research is required to determine a suitable biological response modifier leading to therapeutic effects. The cytokine content of fracture haematoma gives insight into processes occurring in the initial stages of fracture healing. Manipulation of signalling molecules represents a promising pathway to target future therapies aiming to upregulate the osteogenesis.

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Section: Discussionmentioning

confidence: 99%

The cytokines and micro‐environment of fracture haematoma: Current evidence

Walters

Pountos

Giannoudis

2017

J Tissue Eng Regen Med

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“…TGF-βs can display pro- and anti-inflammatory activity depending on their context, and are critical to wound healing, immune responses, and fracture healing. Mice deficient in Smad3, a signaling molecule in the TGF-β pathway, have more rapid fracture repair with less cartilage formation in the callus, accompanied by increased osteogenesis and reduced chondrogenesis (Kawakatsu et al, 2011). Bmp2 has long been known to participate in the signaling pathway that regulates fracture healing.…”

Section: Discussionmentioning

confidence: 99%

Biglycan modulates angiogenesis and bone formation during fracture healing

et al. 2014

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Matrix proteoglycans such as biglycan (Bgn) dominate skeletal tissue and yet its exact role in regulating bone function is still unclear. In this paper we describe the potential role of (Bgn) in the fracture healing process. We hypothesized that Bgn could regulate fracture healing because of previous work showing that it can affect normal bone formation. To test this hypothesis, we created fractures in femurs of 6-week-old male wild type (WT or Bgn+/0) and Bgn-deficient (Bgn-KO or Bgn−/0) mice using a custom-made standardized fracture device, and analyzed the process of healing over time. The formation of a callus around the fracture site was observed at both 7 and 14 days post-fracture in WT and Bgn-deficient mice and immunohistochemistry revealed that Bgn was highly expressed in the fracture callus of WT mice, localizing within woven bone and cartilage. Micro-computed tomography (μCT) analysis of the region surrounding the fracture line showed that the Bgn-deficient mice had a smaller callus than WT mice. Histology of the same region also showed the presence of less cartilage and woven bone in the Bgn-deficient mice compared to WT mice. Picrosirius red staining of the callus visualized under polarized light showed that there was less fibrillar collagen in the Bgn-deficient mice, a finding confirmed by immunohistochemistry using antibodies to type I collagen. Interestingly, real time RT-PCR of the callus at 7 days post-fracture showed a significant decrease in relative vascular endothelial growth factor A (VEGF) gene expression by Bgn-deficient mice as compared to WT. Moreover, VEGF was shown to bind directly to Bgn through a solid-phase binding assay. The inability of Bgn to directly enhance VEGF-induced signaling suggests that Bgn has a unique role in regulating vessel formation, potentially related to VEGF storage or stabilization in the matrix. Taken together, these results suggest that Bgn has a regulatory role in the process of bone formation during fracture healing, and further, that reduced angiogenesis could be the molecular basis.

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“…It is not clear whether any of these defects result from increased BMP signaling. However, it has recently been reported that loss of Smad3 accelerates early bone fracture healing in mice, partly by promoting osteogenesis, which is a BMP-driven process (28,41).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Inhibits Bone Morphogenetic Protein-Induced Transcription through Novel Phosphorylated Smad1/5-Smad3 Complexes

Grönroos

Kingston

Ramachandran

et al. 2012

Molecular and Cellular Biology

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In vivo cells receive simultaneous signals from multiple extracellular ligands and must integrate and interpret them to respond appropriately. Here we investigate the interplay between pathways downstream of two transforming growth factor ␤ (TGF-␤) superfamily members, bone morphogenetic protein (BMP) and TGF-␤. We show that in multiple cell lines, TGF-␤ potently inhibits BMP-induced transcription at the level of both BMP-responsive reporter genes and endogenous BMP target genes. This inhibitory effect requires the TGF-␤ type I receptor ALK5 and is independent of new protein synthesis. Strikingly, we show that Smad3 is required for TGF-␤'s inhibitory effects, whereas Smad2 is not. We go on to demonstrate that TGF-␤ induces the formation of complexes comprising phosphorylated Smad1/5 and Smad3, which bind to BMP-responsive elements in vitro and in vivo and mediate TGF-␤-induced transcriptional repression. Furthermore, loss of Smad3 confers on TGF-␤ the ability to induce transcription via BMP-responsive elements. Our results therefore suggest that not only is Smad3 important for mediating TGF-␤'s inhibitory effects on BMP signaling but it also plays a critical role in restricting the transcriptional output in response to TGF-␤.

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Loss of Smad3 gives rise to poor soft callus formation and accelerates early fracture healing

Cited by 18 publications

References 35 publications

The cytokines and micro‐environment of fracture haematoma: Current evidence

The cytokines and micro‐environment of fracture haematoma: Current evidence

Biglycan modulates angiogenesis and bone formation during fracture healing

Transforming Growth Factor β Inhibits Bone Morphogenetic Protein-Induced Transcription through Novel Phosphorylated Smad1/5-Smad3 Complexes

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