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

Andreev D, Liu M, Weidner D, Kachler K, Faas M, Grüneboom A, Schlötzer-Schrehardt U, Munoz LE, Steffen U, Grötsch B, Killy B, Krönke G, Luebke AM, Niemeier A, Wehrhan F, Lang R, Schett G, Bozec A (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 130

Pages Range: 4811-4830

Journal Issue: 9

DOI: 10.1172/JCI134214

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 damageassociated 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.

Authors with CRIS profile

Darja Andreev Department of Medicine 3 – Rheumatology and Immunology Mengdan Liu Professur für Experimentelle Immuntherapie Maria Faas Professur für Immunologie Ursula Schlötzer-Schrehardt Medizinische Fakultät Luis Munoz Becerra Department of Medicine 3 – Rheumatology and Immunology Ulrike Steffen Department of Medicine 3 – Rheumatology and Immunology Bettina Grötsch Department of Medicine 3 – Rheumatology and Immunology Barbara Killy
Gerhard Krönke Department of Medicine 3 – Rheumatology and Immunology Falk Wehrhan Department of Oral and Cranio-Maxillofacial Surgery Roland Lang Professur für Angeborene Immunität und Pathogenerkennung Georg Schett Lehrstuhl für Innere Medizin III Aline Bozec Professur für Experimentelle Immuntherapie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

J076: The role of itaconate-mediated metabolic reprogramming in osteoclasts Oct. 16, 2019 - April 15, 2022

Involved external institutions

Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE)

How to cite

APA:

Andreev, D., Liu, M., Weidner, D., Kachler, K., Faas, M., Grüneboom, A.,... Bozec, A. (2020). Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin. Journal of Clinical Investigation, 130(9), 4811-4830. https://doi.org/10.1172/JCI134214

MLA:

Andreev, Darja, et al. "Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin." Journal of Clinical Investigation 130.9 (2020): 4811-4830.

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