The sclerostin family: multi-compartmental orchestrators of skeletal and systemic homeostasis

The skeleton is regarded as a dynamic endocrine organ, making the sclerostin family a critical multi-compartmental regulator governed by epigenetic mechanisms such as DNA methylation and histone deacetylase (HDAC) activity. However, the diverse roles of these osteokines across skeletal, vascular, and malignant niches generate a set of complex biological paradoxes. This review resolves these contradictions by defining a core structural bifurcation within the cystine-knot scaffold: Loop 3 serves as the primary inhibitor of bone formation, whereas Loop 2 sustains vascular integrity via the anti-inflammatory axis mediated by apolipoprotein E receptor 2 (ApoER2). In osteo-oncology, we synthesize current evidence supporting a context-dependent functional dichotomy of these factors. Endogenous sclerostin acts as a tumor suppressor in primary osteosarcoma but functions as a metastatic promoter in Wnt-responsive breast cancer, and acts synergistically with Dickkopf-1 (DKK1) to drive severe osteolysis in multiple myeloma (MM). We further detail an intracellular regulatory mechanism whereby nuclear sclerostin domain-containing 1 (SOSTDC1) safeguards chromatin stability under genotoxic stress, thereby enhancing chemoresistance in malignant cells. Finally, we propose a shift toward next-generation domain-specific therapeutics, including Loop 3-selective aptamers and acid-responsive nanosystems, to uncouple skeletal regeneration from systemic risks and advance precision targeted therapy in bone oncology.