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Neoplasia. 2018 Jan;20(1):32-43. doi: 10.1016/j.neo.2017.11.002. Epub 2017 Nov 27.

BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation.

Author information

1
Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
3
Department of Urology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Chemical Engineering and Biotechnology and Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan.
4
Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Urology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
7
Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: slin@mdanderson.org.
8
Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rlsatcher@mdanderson.org.

Abstract

BACKGROUND:

Bone metastasis is common in renal cell carcinoma (RCC), and the lesions are mainly osteolytic. The mechanism of bone destruction in RCC bone metastasis is unknown.

METHODS:

We used a direct intrafemur injection of mice with bone-derived 786-O RCC cells (Bo-786) as an in vivo model to study if inhibition of osteoblast differentiation is involved in osteolytic bone lesions in RCC bone metastasis.

RESULTS:

We showed that bone-derived Bo-786 cells induced osteolytic bone lesions in the femur of mice. We examined the effect of conditioned medium of Bo-786 cells (Bo-786 CM) on both primary mouse osteoblasts and MC3T3-E1 preosteoblasts and found that Bo-786 CM inhibited osteoblast differentiation. Secretome analysis of Bo-786 CM revealed that BIGH3 (Beta ig h3 protein), also known as TGFBI (transforming growth factor beta-induced protein), is highly expressed. We generated recombinant BIGH3 and found that BIGH3 inhibited osteoblast differentiation in vitro. In addition, CM from Bo-786 BIGH3 knockdown cells (786-BIGH3 KD) reduced the inhibition of osteoblast differentiation compared to CM from vector control. Intrafemural injection of mice with 786-BIGH3 KD cells showed a reduction in osteolytic bone lesions compared to vector control. Immunohistochemical staining of 18 bone metastasis specimens from human RCC showed strong BIGH3 expression in 11/18 (61%) and moderate BIGH3 expression in 7/18 (39%) of the specimens.

CONCLUSIONS:

These results suggest that suppression of osteoblast differentiation by BIGH3 is one of the mechanisms that enhance osteolytic lesions in RCC bone metastasis, and raise the possibilty that treatments that increase bone formation may improve therapy outcomes.

PMID:
29190493
PMCID:
PMC5711998
DOI:
10.1016/j.neo.2017.11.002
[Indexed for MEDLINE]
Free PMC Article

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