Are OPG and RANKL involved in human fracture healing?

Köttstorfer, Julia; Thomas, Anita; Gregori, Markus; Kecht, Mathias; Kaiser, Georg; Eipeldauer, Stefan; Sarahrudi, Kambiz

doi:10.1002/jor.22723

Cited by 19 publications

(16 citation statements)

References 15 publications

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“…Our literature search has identified 10 manuscripts reporting the presence of inflammatory cytokines in the fracture haematoma (Currie, Loos, Vrana, Dragan, & Boyd, ; Hauser et al, ; Hauser et al, ; Hoff et al, ; Horst et al, ; Ishikawa et al, ; Kurata et al, ; Sarahrudi et al, ; Wu et al, ; Wu et al, ). Eleven papers report the presence of growth factors (Andrew, ; Brownlow, Reed, & Simpson, ; Groothuis et al, ; Hoff et al, ; Huh et al, ; Köttstorfer et al, ; Sarahrudi et al, ; Sarahrudi et al, ; J. Street et al, ; J. T. Street et al, ; Wildemann et al, ).…”

Section: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

“…Median RANKL concentration was found to be significantly elevated, at 0.18 pmol/L, in fracture haematoma when compared with serum at a concentration of 0.03 pmol/L (Köttstorfer et al, ). Similarly, OPG was found to be significantly higher in fracture haematoma, at 49.33 pmol/L, than peripheral serum at 5.09 pmol/L (Köttstorfer et al, ). A study investigating the expression of the two proteins reported a significant rise in OPG expression, peaking at 24 hr after fracture and again at 7 days (Kon et al, ).…”

Section: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

“…With strong crosstalk between osteoblasts and osteoclasts during bone formation and remodelling, altered OPG and RANKL levels are expected in fracture haematoma (Köttstorfer et al, ). The peaks in OPG levels were correlated with the maximal phase of cartilage formation, as inhibition of bone resorbing cells is desirable at the time point (Kon et al, ).…”

Section: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

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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: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

Section: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

Section: Cytokines and Growth Factor Content Of Fracture Haematomamentioning

confidence: 99%

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

Walters

Pountos

Giannoudis

2017

J Tissue Eng Regen Med

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“…However, other BTM such as CTX, PICP, and OC, have been shown to increase following an initial fall after fracture [32, 33], but we did not find this result in our case series. Few studies have analyzed the serum levels of RANKL and OPG during the fracture healing process, and a high variability of results was found [45–47]. Therefore, our findings suggest that bone repair steps following the physiological fracture healing or a regenerative treatment differ to some extent.…”

Section: Discussionmentioning

confidence: 80%

Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach

Granchi

Gómez‐Barrena

Rojewski

et al. 2017

Stem Cells International

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In this clinical trial, we investigated if biochemical bone turnover markers (BTM) changed according to the progression of bone healing induced by autologous expanded MSC combined with a biphasic calcium phosphate in patients with delayed union or nonunion of long bone fractures. Bone formation markers, bone resorption markers, and osteoclast regulatory proteins were measured by enzymatic immunoassay before surgery and after 6, 12, and 24 weeks. A satisfactory bone healing was obtained in 23 out of 24 patients. Nine subjects reached a good consolidation already at 12 weeks, and they were considered as the “early consolidation” group. We found that bone-specific alkaline phosphatase (BAP), C-terminal propeptide of type I procollagen (PICP), and beta crosslaps collagen (CTX) changed after the regenerative treatment, BAP and CTX correlated to the imaging results collected at 12 and 24 weeks, and BAP variation along the healing course differed in patients who had an “early consolidation.” A remarkable decrease in BAP and PICP was observed at all time points in a single patient who experienced a treatment failure, but the predictive value of BTM changes cannot be determined. Our findings suggest that BTM are promising tools for monitoring cell therapy efficacy in bone nonunions, but studies with larger patient numbers are required to confirm these preliminary results.

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“…33 The RANKL:OPG ratio reflects bone remodeling and homeostasis by comparing the relative expression of RANKL, an osteoclast inducer, and OPG, a decoy receptor, that prevents RANKL from activating osteoclasts. 34 Statistical analysis suggests that the use of clindamycin imparts a protective effect through the increased expression of OPG, regardless of the presence of infection, and that RANK-L:OPG is significantly influenced by the presence of clindamycin, likely through increased OPG expression. In vitro work in human and rat dental cells has demonstrated that IL-10 has antiosteoclastogenic properties by means of increasing OPG and decreasing RANKL mRNA expression, and the high levels of IL-10 observed in the +Inc/-Abx group may contribute to unexpectedly low RANKL production.…”

Section: Discussionmentioning

confidence: 99%

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect

Shah

Smith

Tatara

et al. 2017

Tissue Engineering Part A

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Reconstruction of large bone defects can be complicated by the presence of both infection and local antibiotic administration. This can be addressed through a two-stage reconstructive approach, called the Masquelet technique, that involves the generation of an induced osteogenic membrane over a temporary poly(methyl methacrylate) (PMMA) space maintainer, followed by definitive reconstruction after the induced membrane is formed. Given that infection and antibiotic delivery each have independent effects on local tissue response, the objective of this study is to evaluate the interaction between local clindamycin release and bacterial contamination with regards to infection prevention and the restoration of pro-osteogenic gene expression in the induced membrane. Porous PMMA space maintainers with or without clindamycin were implanted in an 8 mm rat femoral defect model with or without Staphylococcus aureus inoculation for 28 days in a full-factorial study design (four groups, n = 8/group). Culture results demonstrated that 8/8 animals in the inoculated/no antibiotic group were infected at 4 weeks, which was significantly reduced to 1/8 animals in the inoculated/antibiotic group. Quantitative polymerase chain reaction analysis demonstrated that clindamycin treatment restores inflammatory cytokine and growth factor expression to the same levels as the no inoculation/no antibiotic group, demonstrating that clindamycin can ameliorate the negative effects of bacterial inoculation and does not itself negatively impact the expression of important cytokines. Main effect analysis shows that bacterial inoculation and clindamycin treatment have independent and interacting effects on the gene expression profile of the induced membrane, further highlighting that antibiotics play an important role in the regeneration of infected defects apart from their antimicrobial properties.

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Are OPG and RANKL involved in human fracture healing?

Cited by 19 publications

References 15 publications

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

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

Changes of Bone Turnover Markers in Long Bone Nonunions Treated with a Regenerative Approach

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect

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