C-type lectin receptors: bone remodeling and therapeutic potential.

Osteoimmunology explores the interplay between the skeletal system and the immune system. It focuses on the identification of shared signaling pathways and the mechanisms of mutual regulation. Bone homeostasis depends on the balance between the activity of bone-forming osteoblasts and bone-resorbing osteoclasts. Interestingly, the crosstalk between osteoclasts, osteoblasts, osteocytes, and immune cells not only shapes bone remodeling but also influences immune responses. A central pathway in osteoclast differentiation is the receptor activator of nuclear factor-κB ligand (RANKL) signaling, which induces NFATc1, the master transcription factor of osteoclastogenesis. Recent evidence shows that immunoreceptor tyrosine-based activation motif (ITAM)-containing co-receptors enhance RANKL-induced signaling, underscoring their essential role in osteoclast activation and differentiation. Increasing attention has been directed toward C-type lectin receptors (CLRs), such as Dectin-1, Mincle, and DC-SIGN. These receptors have historically been recognized for their functions in antifungal and antibacterial immunity. However, their expression on both immune cells and osteoclasts links CLR signaling to osteoclastogenesis, as CLR engagement signals through ITAM pathways, contributing to NFAT activation. Therefore, CLRs could function as co-receptors for RANKL in human osteoclast biology, although the underlying mechanisms remain poorly defined. This review synthesizes current knowledge on CLR signaling and its role in osteoclastogenesis. It examines how CLR-mediated pathways influence bone resorption and evaluates their therapeutic potential. Finally, the review discusses the challenges of translating these insights into clinical applications and highlights emerging strategies for targeting CLRs in bone-related pathologies.