Abstract
Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.
Highlights
Giant cell tumor of bone (GCTB) is a common type of primary bone tumor and usually occurs at the metaphysis of the long bones of the limbs, including the distal femur, proximal femur and proximal tibia [1]
SRGN expression and secretion are upregulated in GCTB To study GCTB, we established a series of primary stromal cell lines from clinical GCTB tumors (Supplementary Fig. S1A)
The analysis identified 23 differentially secreted proteins, among which secreted phosphoprotein 1 (SPP1), growth differentiation factor 15 (GDF15) and SRGN ranked at the top of upregulated proteins in GCTB (Fig. 1C)
Summary
Giant cell tumor of bone (GCTB) is a common type of primary bone tumor and usually occurs at the metaphysis of the long bones of the limbs, including the distal femur, proximal femur and proximal tibia [1]. MGCs are highly similar in both morphology and function to osteoclasts and are considered as the main cause of bone damage by GTCB, while the stromal cells are the neoplastic component in the tumor [4,5,6]. Current studies show that the neoplastic cells of GCTB are originated from osteoblast-like mesenchymal precursor cells [7, 8] and often harbor the highly specific histone 3.3 G34W (H3.3G34W) mutation [9]. They are known to induce the formation of MGCs from the mononuclear precursors of osteoclasts [10,11,12]. How the stromal cells drive osteoclastogenesis from monocytes is incompletely understood
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