A Fully Human Engineered Bone Niche With Endogenous Osteoclastogenesis Reveals Osteoclast-Dependent Osteomimicry in Prostate Cancer Cells.

Abstract

Bone is the predominant site of metastasis in advanced prostate cancer (PCa), yet the mechanisms governing tumor-bone interactions remain incompletely understood, thanks in part to the scarcity of relevant models. The role played by osteoclasts in such interactions is especially obscure. A modular human three-dimensional (3D) in vitro bone niche model was developedThe model integrates osteoblasts and osteoclasts within a mineralized scaffold, recreating an endosteal-like microenvironment for co-culture with PCa cell lines and patient-derived organoids (PDOs). The engineered construct maintains osteoblastic differentiation and supports osteoclastogenesis, confirmed by lineage markers including osteocalcin, osteopontin (OPN), and tartrate-resistant acid phosphatase (TRAP). Co-culture with PCa cells downregulates osteoblast- and osteoclast-associated genes (IBSP, OPN, TRAP) in bone cells, suggesting tumor-mediated suppression of bone remodeling. Conversely, co-cultured PCa cells exhibit niche-dependent osteomimicry, characterized by upregulation of osteoblastic (SPARC, BGLAP) and osteoclastic (TRAP) markers and strongly regulated by the presence of osteoclasts. The platform also supports engraftment and proliferation of PDOs without exogenous PCa-specific growth factors, underscoring its translational relevance. This osteoblastic-osteoclastic niche model provides a human system that captures PCa-bone cell interactions in a clinically relevant context, with potential utility for mechanistic and translational studies.