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Cited by 17Osteoarthritis Treatment and MechanismsNeuropeptides and Animal PhysiologyPain Mechanisms and Treatments

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The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis

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Hildebrandt, Alexander, Dietrich, Tamara, Weber, Jérôme, Günderoth, Mara Meyer, Zhou, Sijia, Fleckenstein, Florian N., Jiang, Shan, Winkler, Tobias, Duda, Georg N., Tsitsilonis, Serafeim, Keller, Johannes, Maleitzke, Tazio·2023·Arthritis Research & Therapy
DOI 10.1186/s13075-023-03215-3PMC PMC10722726
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Abstract

Background: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. Methods: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP−/−aged) were compared to, first, age-matched wild type (WT aged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP−/−CTRL) and non-OA WT animals (WT CTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. Results: WT aged mice exhibited elevated αCGRP serum levels compared to young WT CTRL animals. Marked signs of OA-induced cartilage destruction were seen in WT aged animals, while αCGRP−/−aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WT aged but not in αCGRP−/−aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. Conclusions: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

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  • CGRP and SP can directly reprogram synovial macrophages and chondrocytes, promoting proinflammatory transcriptional programs and up-regulating matrix-degrading enzymes.

    “CGRP and SP can directly reprogram synovial macrophages and chondrocytes, promoting proinflammatory transcriptional programs and up-regulating matrix-degrading enzymes [64,65]”

    From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [65]

    The Results (page not provided) link αCGRP to higher inflammatory gene expression and cartilage-degrading markers in aged mouse knee joints. The paper does not establish that CGRP directly reprograms synovial macrophages or chondrocytes, and these passages provide no support for the claim about SP. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Metadata

Authors
Hildebrandt, A., Dietrich, T., Weber, J., Günderoth, M. M., Zhou, S., Fleckenstein, F. N., Jiang, S., Winkler, T., Duda, G. N., Tsitsilonis, S., Keller, J., & Maleitzke, T.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
  • University of Copenhagen (DK)
Corresponding author
Maleitzke, Tazio
ORCID
Venue
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-12-15
Volume
25
Issue
1
Pages
244-244
ISSN
  • 1478-6354 (ISSN-L)
  • 1478-6362
DOI
10.1186/s13075-023-03215-3
PMC
PMC10722726
OpenAlex
W4389818654
Cited by
17
References
1
Citations by year
2026: 11 · 2025: 4 · 2024: 2
FWCI
3.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Arthritis Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (DFG KE 2179)
  • Else Kröner-Fresenius-Stiftung (EKFS 2017_A22)
  • Stiftung Oskar-Helene-Heim
  • Charité - Universitätsmedizin Berlin
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Keywords
age-related osteoarthritis, primary knee osteoarthritis, cartilage degeneration, subchondral sclerosis, bone loss, inflammatory cytokines, matrix metalloproteinases, RANKL, CXCL12/CXCR4 axis, anti-CGRP therapy, vasoactive neuropeptides
MeSH terms
Animals, Arthritis, Experimental, Bone and Bones, Cartilage, Cartilage, Articular, Disease Models, Animal, Inflammation, Calcitonin Gene-Related Peptide, Osteoarthritis, Knee, Mice

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