Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gα_q and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor–related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.

Progressive multi-vertebral osteolysis, frequently misdiagnosed as malignancy or tuberculosis, can also be driven by a previously unrecognized infectious trigger. Here we demonstrate that sparganosis induces pronounced IgE-dependent osteoclastogenesis and severe bone destruction. Single-cell RNA analysis of peripheral blood mononuclear cells identified the immune cell landscape of spinal sparganosis (SS) and the immunoglobulin-related pathways upregulated in naïve B cells derived from SS. Notably, the sparganosis triggers osteoclast activation and subsequent bone destruction. IgE was found at a dramatically high level in SS and played a critical driver of osteoclast activity and osteolysis. Notably, >90% of this IgE proved non-plerocercoid-specific, indicating that infection triggers an IgE hyper-response which sustains osteoclast activation. Mechanistically, IgE binding to the low-affinity Fc epsilon receptor II (FcεRII) using its Fc part, followed by upregulating the expression and nuclear translocation of NFATc1 via activating the AKT/ERK signaling pathway, promotes osteoclast precursor cells differentiation and bone resorption. Importantly, Omalizumab, the only marketed drug of monoclonal anti-IgE antibodies, could compromise the osteoclastogenesis induced by IgE and SS plasma. These findings provide novel insights into the immunopathological mechanisms of IgE in promoting osteolytic destruction in SS, and Omalizumab is a candidate for a potential therapeutic strategy to alleviate osteolysis in SS patients.