Augmented osteolysis in SPARC-deficient mice with bone-residing prostate cancer.
Prostate cancer preferentially metastasizes to bone, which is rich in structural and matricellular proteins capable of altering prostate cancer progression. This study explores the role of the bone stromal matricellular protein SPARC (osteonectin/BM-40) in the progression of bone metastatic prostate cancer. Quantification of bone destruction analyzed by micro-computed tomography showed augmented osteoclastic resorption, characterized by decreases in several morphometric bone parameters in SPARC knock out (KO) tibiae harboring RM1 murine prostate cancer cells compared with wild type (WT) animals. Tumor progression stimulated osteoclast formation, which was augmented in SPARC KO mice. In vitro differentiation of SPARC KO osteoclasts indicated accelerated progenitor expansion and formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells with increased resorptive capacity, a mechanism resulting in enhanced tumor-induced bone loss in vivo. Whereas altered bone structure due to SPARC KO played a role in increased osteolysis, the enhanced osteolysis was primarily the result of increased resorption by SPARC KO osteoclasts. Our findings indicate that bone stromal SPARC suppresses tumor-induced bone lesion expansion by limiting osteoclast maturation and function.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
N Patrick
NP
McCabe
Bethany A
BA
Kerr
Maria
M
Madajka
Amit
A
Vasanji
Tatiana V
TV
Byzova
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000556:secondary; D001862:Bone Resorption / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D010014:Osteolysis / Q000473:pathology*; D015676:Osteonectin / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D015676:Osteonectin
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