Cited by 188Bone Metabolism and DiseasesImmune Response and InflammationOsteomyelitis and Bone Disorders Research

Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin

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Andreev, Darja, Liu, Mengdan, Weidner, Daniela, Kachler, Katerina, Faas, Maria, Grüneboom, Anika, Schlötzer-Schrehardt, Ursula, Muñoz, Luis E. +10 more·2020·Journal of Clinical Investigation

Abstract

Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damage-associated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necrotic osteocytes in vitro and in vivo. RNA sequencing and metabolic analyses demonstrated that Mincle activation triggers osteoclastogenesis via ITAM-based calcium signaling pathways, skewing osteoclast metabolism toward oxidative phosphorylation. Deletion of Mincle in vivo effectively blocked the activation of osteoclasts after induction of osteocyte death, improved fracture repair, and attenuated inflammation-mediated bone loss. Furthermore, in patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity. Taken together, these data point to what we believe is a novel DAMP-mediated process that allows osteoclast activation and bone loss in the context of osteocyte death.

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  • DAMPs can directly regulate osteoclast formation by activating the membrane-bound C-type lectin receptor Mincle; Mincle activation triggers calcium signaling and oxidative phosphorylation in osteoclasts, inducing osteoclast differentiation.

    “DAMPs can directly regulate osteoclast formation by activating the membrane-bound C-type lectin receptor Mincle. Mincle activation triggers calcium signaling and oxidative phosphorylation in osteoclasts, inducing osteoclast differentiation.74”

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Authors
Andreev, D., Liu, M., Weidner, D., Kachler, K., Faas, M., Grüneboom, A., Schlötzer-Schrehardt, U., Muñoz, L. E., Steffen, U., Grötsch, B., Killy, B., Krönke, G., Luebke, A. M., Niemeier, A., Wehrhan, F., Lang, R., Schett, G., & Bozec, A.
Affiliations
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
Venue
Journal of Clinical Investigation
Published
2020-08-10
Volume
130
Issue
9
Pages
4811-4830
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
OpenAlex
W3047914933
Cited by
188
References
68
Citations by year
2026: 25 · 2025: 38 · 2024: 41 · 2023: 35 · 2022: 24 · 2021: 19 · 2020: 6
FWCI
6.81
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft (CRC‐1181, FOR 2886 (TP02, FOR2886, BO‐3811/5‐1, BO-3811/6-1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
Keywords
osteoclastogenesis, Mincle, damage-associated molecular patterns, bone loss, avascular necrosis, fracture healing, ITAM signaling, calcium signaling, oxidative phosphorylation, RANKL
MeSH terms
RNA-Seq, Animals, Bone Resorption, Membrane Proteins, Necrosis, Osteoclasts, Osteocytes, Mice, Knockout, Lectins, C-Type, Mice

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