Local Wnt3a treatment restores bone regeneration in large osseous defects after surgical debridement of osteomyelitis

Wagner, Johannes Maximilian; Reinkemeier, Felix; Dadras, Mehran; Wallner, Christoph; Huber, Julika; Sogorski, Alexander; Sacher, Maxi; Schmidt, Sonja; Drysch, Marius; Dittfeld, Stephanie; Becerikli, Mustafa; Becker, Kathrin; Rauch, Nicole; Lehnhardt, Marcus; Behr, Björn

doi:10.1007/s00109-020-01924-9

Cited by 12 publications

(8 citation statements)

References 55 publications

(75 reference statements)

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“…Finally, many other biomarkers, such as IL-6, retinol-binding protein, prealbumin, and PSP, among others, have been studied with contradictory evidence and no clear practical usefulness [ 1 , 11 , 22 , 24 ]. The expression of DKK1 has been recently evaluated in the context of osteomyelitis [ 39 ] and infectious processes [ 40 - 42 ] but as far as we know, there exist no reports of spinal infections. We include this marker in the systematic review to confirm that there exist no previous studies in this respect as to establish a starting point for a research line in this direction.…”

Section: Discussionmentioning

confidence: 99%

The Inflammatory Biomarkers Behavior Profile of Patients Following Elective Degenerative Spine Surgery and Differences Compared to Those Coursing With a Postoperative Spinal Infection: Protocol for a Systematic Review

Rangel¹,

Ponce²,

Chew³

et al. 2023

JMIR Res Protoc

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Background The incidence of postoperative spinal infection (PSI) ranges from 0% to 10%, with devastating effects on the patient prognosis because of higher morbidity while increasing costs to the health care system. PSIs are elusive and difficult to diagnose, especially in the early postoperative state, because of confusing clinical symptoms, rise in serum biomarkers, or imaging studies. Current research on diagnosis has focused on serum biomarkers; nevertheless, most series rely on retrospective cohorts where biomarkers are studied individually and at different time points. Objective This paper presents the protocol for a systematic review that aims to determine the inflammatory biomarker behavior profile of patients following elective degenerative spine surgery and their differences compared to those coursing with PSIs. Methods The proposed systematic review will follow the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. This protocol was registered at PROSPERO on January 19, 2022. We will include studies related to biomarkers in adult patients operated on for degenerative spinal diseases and those developing PSIs. The following information will be extracted from the papers: (1) study title; (2) study author; (3) year; (4) evidence level; (5) research type; (6) diagnosis group (elective postoperative degenerative disease or PSI); (7a) region (cervical, thoracic, lumbosacral, and coccygeal); (7b) type of infection by anatomical or radiological site; (8) surgery type (including instrumentation or not); (9) number of cases; (10) mean age or individual age; (11) individual serum biomarker values from the preoperative state up to 90 days postoperative for both groups, including (10a) interleukin-6, (10b) presepsin, (10c) erythrocyte sedimentation rate, (10d) leukocyte count, (10e) neutrophil count, (10f) C-reactive protein, (10g) serum amyloid, (10h) white cell count, (10i) albumin, (10j) prealbumin, (10k) procalcitonin, (10l) retinol-associated protein, and (10m) Dickkopf-1; (11) postoperative days at symptoms or diagnosis; (12) type of organism; (13) day of starting antibiotics; (14) duration of treatment; and (15) any biases (including comorbidities, especially those affecting immunological status). All data on biomarkers will be presented graphically over time. Results No ethical approval will be required, as this review is based on published data and does not involve interaction with human participants. The search for this systematic review commenced in February 2021, and we expect to publish the findings in mid-2023. Conclusions This study will provide the behavior profile of biomarkers for PSI and patients following elective surgery for degenerative spinal diseases from the preoperative period up to 90 days postoperative, providing cutoff values on the day of diagnosis. This research will provide clinicians with highly trustable cutoff reference values for PSI diagnosis. Finally, we expect to provide a basis for future research on biomarkers that help diagnose more accurately and in a timely manner in the early stages of illness, ultimately impacting the patient’s physical and mental health, and reducing the disease burden. Trial Registration PROSPERO CRD42022304645; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=304645 International Registered Report Identifier (IRRID) DERR1-10.2196/41555

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Section: Discussionmentioning

confidence: 99%

The Inflammatory Biomarkers Behavior Profile of Patients Following Elective Degenerative Spine Surgery and Differences Compared to Those Coursing With a Postoperative Spinal Infection: Protocol for a Systematic Review

Rangel¹,

Ponce²,

Chew³

et al. 2023

JMIR Res Protoc

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“…Mice of the uninjured bone group did not receive any operation. Euthanasia was performed by cervical dislocation according to national and international laws and guidelines d3 and d7 postoperation, which represents an early and late time point during bone regeneration 15,16 . Each group consisted of at least five animals.…”

Section: Methodsmentioning

confidence: 99%

TGF‐beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration

Becerikli

Reinkemeier

Dadras

et al. 2021

Journal Orthopaedic Research

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Bone regeneration and fracture healing are impaired in diabetic patients due to defective functions of associated cells. Thus, the search for molecular causes and new treatment strategies are of particular clinical relevance. We investigated the gene expression profile of bones from type 2 diabetic (db−/db−) mice and wild‐type (wt) mice by comparative microarray analyses before and after placing tibial defects and examined the expression of several osteogenesis‐ and osteoclastogenesis‐related markers by quantitative real‐time polymerase chain reaction. In regenerating wt bones, pathways related to, for example, inhibition of matrix metalloproteases were activated, whereas in db−/db− bones activation of pathways related to, for example, osteoarthritis, transforming growth factor‐beta (Tgfb), or hypoxia‐inducible factor 1a were detected during regeneration. We defined the Tgfb pathway as a potential therapeutic target and locally applied a single dose (0.5 µg) of the Tgfb 1, 2, and 3 neutralizing antibody 1D11 on tibial defects in db−/db− mice (n = 7). Seven days postoperation, histological and immunohistochemical stainings were performed. Decreased bone regeneration, osteogenic differentiation, osteoclast invasion, and angiogenesis in db−/db− mice were significantly restored by local 1D11 application in comparison to the phosphate‐buffered saline controls. Thus, local treatment of db−/db− bony defects with Tgfb neutralizing antibody 1D11 might be considered a good candidate for the successful acceleration of bone regeneration.

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“…However, the use of Wnt/β-catenin inhibitors, such as Quercitin, reduce MSC proliferation and multipotency by favoring their osteogenic commitment and inhibiting both the chondrogenic and the adipogenic differentiation (Qu et al, 2013;Narcisi et al, 2015;Jothimani et al, 2020;Volleman et al, 2020). This model failed to explain the positive contribution of canonical Wnt in bone homeostasis in vivo (Wagner et al, 2020). Liu et al suggested a role for Wnt/β-catenin activation levels; in fact, they observed a promoting effect with low concentrations of Wnt3a during osteogenic differentiation, through the regulation of key transcription factors such as RUNX2 and Osterix (Osx), while higher concentrations suppressed both osteogenesis and adipogenesis (Gaur et al, 2005;Liu et al, 2009).…”

Section: The Wnt Signaling In Mscsmentioning

confidence: 99%

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

Kamga

Bazzoni

Collo

et al. 2021

Front. Cell Dev. Biol.

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Notch and Wnt signaling are highly conserved intercellular communication pathways involved in developmental processes, such as hematopoiesis. Even though data from literature support a role for these two pathways in both physiological hematopoiesis and leukemia, there are still many controversies concerning the nature of their contribution. Early studies, strengthened by findings from T-cell acute lymphoblastic leukemia (T-ALL), have focused their investigation on the mutations in genes encoding for components of the pathways, with limited results except for B-cell chronic lymphocytic leukemia (CLL); in because in other leukemia the two pathways could be hyper-expressed without genetic abnormalities. As normal and malignant hematopoiesis require close and complex interactions between hematopoietic cells and specialized bone marrow (BM) niche cells, recent studies have focused on the role of Notch and Wnt signaling in the context of normal crosstalk between hematopoietic/leukemia cells and stromal components. Amongst the latter, mesenchymal stromal/stem cells (MSCs) play a pivotal role as multipotent non-hematopoietic cells capable of giving rise to most of the BM niche stromal cells, including fibroblasts, adipocytes, and osteocytes. Indeed, MSCs express and secrete a broad pattern of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation and differentiation. Herein, we provide an overview on recent advances on the contribution of MSC-derived Notch and Wnt signaling to hematopoiesis and leukemia development.

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Local Wnt3a treatment restores bone regeneration in large osseous defects after surgical debridement of osteomyelitis

Cited by 12 publications

References 55 publications

The Inflammatory Biomarkers Behavior Profile of Patients Following Elective Degenerative Spine Surgery and Differences Compared to Those Coursing With a Postoperative Spinal Infection: Protocol for a Systematic Review

The Inflammatory Biomarkers Behavior Profile of Patients Following Elective Degenerative Spine Surgery and Differences Compared to Those Coursing With a Postoperative Spinal Infection: Protocol for a Systematic Review

TGF‐beta pathway inhibition as the therapeutic acceleration of diabetic bone regeneration

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

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