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Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor.
- Source :
-
Bone research [Bone Res] 2024 Jun 07; Vol. 12 (1), pp. 35. Date of Electronic Publication: 2024 Jun 07. - Publication Year :
- 2024
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Abstract
- DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Cytoskeleton metabolism
Mice, Knockout
Mice, Inbred C57BL
Membrane Proteins metabolism
Membrane Proteins genetics
rac GTP-Binding Proteins metabolism
rac GTP-Binding Proteins genetics
Membrane Glycoproteins metabolism
Membrane Glycoproteins genetics
Receptors, Immunologic metabolism
Receptors, Immunologic genetics
Immunoglobulins
Osteoclasts metabolism
Signal Transduction
Macrophage Colony-Stimulating Factor metabolism
Macrophage Colony-Stimulating Factor genetics
rap1 GTP-Binding Proteins metabolism
rap1 GTP-Binding Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2095-4700
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bone research
- Publication Type :
- Academic Journal
- Accession number :
- 38849345
- Full Text :
- https://doi.org/10.1038/s41413-024-00340-w