Hardaway Aimalie L, Herroon Mackenzie K, Rajagurubandara Erandi, Podgorski Izabela
Department of Pharmacology, Wayne State University School of Medicine, 540 E. Canfield, Rm 6304, Detroit, MI, 48201, USA.
Clin Exp Metastasis. 2015 Apr;32(4):353-68. doi: 10.1007/s10585-015-9714-5. Epub 2015 Mar 24.
Increased bone marrow adiposity is a common feature of advanced age, obesity and associated metabolic pathologies. Augmented numbers of marrow adipocytes positively correlate with dysregulated bone remodeling, also a well-established complication of metastatic disease. We have shown previously that marrow adiposity accelerates prostate tumor progression in the skeleton and promotes extensive destruction of the bone; however, the factors behind adipocyte-driven osteolysis in the skeletal tumor microenvironment are not currently known. In this study, utilizing in vivo diet-induced models of bone marrow adiposity, we reveal evidence for positive correlation between increased marrow fat content, bone degradation by ARCaP(M) and PC3 prostate tumors, and augmented levels of host-derived CXCL1 and CXCL2, ligands of CXCR2 receptor. We show by in vitro osteoclastogenesis assays that media conditioned by bone marrow adipocytes is a significant source of CXCL1 and CXCL2 proteins. We also demonstrate that both the adipocyte-conditioned media and the recombinant CXCL1 and CXCL2 ligands efficiently accelerate osteoclast maturation, a process that can be blocked by neutralizing antibodies to each of the chemokines. We further confirm the contribution of CXCR2 signaling axis to adiposity-driven osteoclastogenesis by blocking fat cell-induced osteoclast differentiation with CXCR2 antagonist or neutralizing antibodies. Together, our results link CXCL1 and CXCL2 chemokines with bone marrow adiposity and implicate CXCR2 signaling in promoting effects of marrow fat on progression of skeletal tumors in bone.
骨髓脂肪增多是衰老、肥胖及相关代谢性疾病的常见特征。骨髓脂肪细胞数量增加与骨重塑失调呈正相关，而骨重塑失调也是转移性疾病的一个公认并发症。我们之前已经表明，骨髓脂肪增多会加速骨骼中前列腺肿瘤的进展，并促进骨骼的广泛破坏；然而，目前尚不清楚骨骼肿瘤微环境中脂肪细胞驱动的骨溶解背后的因素。在本研究中，利用体内饮食诱导的骨髓脂肪增多模型，我们揭示了骨髓脂肪含量增加、ARCaP(M)和PC3前列腺肿瘤导致的骨降解以及宿主来源的CXCL1和CXCL2（CXCR2受体的配体）水平升高之间存在正相关的证据。我们通过体外破骨细胞生成试验表明，骨髓脂肪细胞条件培养基是CXCL1和CXCL2蛋白的重要来源。我们还证明，脂肪细胞条件培养基以及重组CXCL1和CXCL2配体均能有效加速破骨细胞成熟，这一过程可被针对每种趋化因子的中和抗体阻断。我们通过用CXCR2拮抗剂或中和抗体阻断脂肪细胞诱导的破骨细胞分化，进一步证实了CXCR2信号轴对脂肪增多驱动的破骨细胞生成的作用。总之，我们的结果将CXCL1和CXCL2趋化因子与骨髓脂肪增多联系起来，并表明CXCR2信号在骨髓脂肪对骨骼中骨肿瘤进展的促进作用中发挥作用。
