Role of C-type lectin molecules in bone homeostasis
Immunology
Final Report Abstract
Our study explores the link between osteocyte death and bone loss, emphasizing the role of the C-type lectin receptor Mincle in osteoclastogenesis. Osteocytes, the predominant bone cells, regulate bone remodeling through the secretion of factors that influence osteoclast differentiation. When osteocytes die, especially through necrosis, they release damageassociated molecular patterns (DAMPs) that could activate osteoclasts, leading to bone resorption and pathological bone loss. Experiments with Dmp1-Cre mice demonstrated that induced osteocyte necrosis increased osteoclast formation and activity, as confirmed by histological and micro-CT analyses. Serum starvation-induced necrosis in the IDG-SW3 osteocyte cell line further enhanced osteoclastogenesis when necrotic supernatants were added to osteoclast cultures. Mincle expression was significantly upregulated in osteoclasts exposed to necrotic, but not apoptotic or viable, osteocytes. Mincle knockout (KO) mice exhibited higher bone mass and reduced osteoclast numbers, indicating a defect in osteoclast precursor fusion and differentiation. In human disease models, increased Mincle expression was observed in osteoclasts from patients with osteonecrosis of the femoral head (ONFH) and medication-related osteonecrosis of the jaw (MRONJ), correlating with osteoclast activity markers but not early osteoclast markers, suggesting a specific role in response to osteocyte necrosis. Mechanistically, RNA sequencing revealed that Mincle engagement in osteoclasts activates calcium signaling and oxidative phosphorylation pathways, crucial for osteoclast differentiation and function. Additionally, Mincle KO mice showed improved fracture repair and less bone loss in rheumatoid arthritis models compared to wild-type mice, underscoring Mincle’s role in pathological bone resorption. The study concludes that Mincle is a critical mediator linking osteocyte necrosis to osteoclast activation and subsequent bone loss, proposing that targeting Mincle could offer a therapeutic strategy for bone diseases characterized by excessive osteocyte death and osteoclast activity, thus providing significant insight into the molecular mechanisms underlying bone resorption associated with osteocyte necrosis.
Publications
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Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin. Journal of Clinical Investigation, 130(9), 4811-4830.
Andreev, Darja; Liu, Mengdan; Weidner, Daniela; Kachler, Katerina; Faas, Maria; Grüneboom, Anika; Schlötzer-Schrehardt, Ursula; Muñoz, Luis E.; Steffen, Ulrike; Grötsch, Bettina; Killy, Barbara; Krönke, Gerhard; Luebke, Andreas M.; Niemeier, Andreas; Wehrhan, Falk; Lang, Roland; Schett, Georg & Bozec, Aline
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Hypoxia-Inducible Factors Regulate Osteoclasts in Health and Disease. Frontiers in Cell and Developmental Biology, 9.
Meng, Xianyi; Wielockx, Ben; Rauner, Martina & Bozec, Aline
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Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis. Annals of the Rheumatic Diseases, 80(4), 451-468.
Andreev, Darja; Liu, Mengdan; Kachler, Katerina; Llerins, Perez Mireia; Kirchner, Philipp; Kölle, Julia; Gießl, Andreas; Rauber, Simon; Song, Rui; Aust, Oliver; Grüneboom, Anika; Kleyer, Arnd; Cañete, Juan D.; Ekici, Arif; Ramming, Andreas; Finotto, Susetta; Schett, Georg & Bozec, Aline
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Estrogen-mediated downregulation of HIF-1α signaling in B lymphocytes influences postmenopausal bone loss. Bone Research, 10(1).
Meng, Xianyi; Lin, Zhen; Cao, Shan; Janowska, Iga; Sonomoto, Koshiro; Andreev, Darja; Katharina, Knab; Wen, Jinming; Knaup, Karl Xaver; Wiesener, Michael Sean; Krönke, Gerhard; Rizzi, Marta; Schett, Georg & Bozec, Aline
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Inflammatory activation of the FcγR and IFNγR pathways co-influences the differentiation and activity of osteoclasts. Frontiers in Immunology, 13.
Groetsch, Bettina; Schachtschabel, Elisabeth; Tripal, Philipp; Schmid, Benjamin; Smith, Ana-Suncana; Schett, Georg & Bozec, Aline
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Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism. Bone, 162, 116468.
Andreev, Darja; Kachler, Katerina; Schett, Georg & Bozec, Aline
