SPARC is a decoy counterpart for c-Fos and is associated with osteoblastic differentiation of bone marrow stromal cells by inhibiting adipogenesis
SPARC is a decoy counterpart for c-Fos and is associated with osteoblastic differentiation of bone marrow stromal cells by inhibiting adipogenesis
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DOI：
10.3892/mmr.2023.12937
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发表时间：
2023-02-01
影响因子：
3.4
通讯作者：
Kato, Yasumasa
中科院分区：
文献类型：
--
作者：
Hatori, Tomoya;Maeda, Toyonobu;Kato, Yasumasa
富含半胱氨酸的酸性分泌蛋白(SPARC)，又称基底膜蛋白40或骨连接蛋白，是一种基质细胞蛋白，不仅以非胶原性蛋白的形式在骨组织中大量存在，而且在非钙化组织中也广泛表达。SPARC定位于细胞内，破坏SPARC基因可以减少骨形成和增加脂肪组织；然而，SPARC抑制脂肪生成的机制尚不清楚。本研究使用骨髓基质细胞系ST2评价SPARC在成脂过程中的细胞内功能。低SPARC产量的ST2细胞克隆后，其内源性激活蛋白-1(AP-1)活性显著高于亲本ST2细胞，矿化结节形成显著低于亲本细胞，脂质积累显著增加。在SPARC-low ST2细胞中，分泌的SPARC与野生型SPARC或前胰蛋白酶的信号肽编码序列一起强制表达显著降低AP-1的转录活性；然而，在没有信号肽序列的情况下，这些降低不被观察到。由短杆菌产生的重组SPARC与c-Fos特异结合，但不与c-Jun结合，并抑制c-Fos/c-Jun与TPA反应元件序列的结合。这些数据表明，SPARC从细胞外间隙被整合到细胞内，作为c-Fos的诱饵对应物，并通过抑制脂肪生成与成骨细胞的形成有关。这些发现可能会为再生医学提供新的见解。
Secreted protein acidic and rich in cysteine (SPARC), also called basement-membrane protein 40 or osteonectin, is a matricellular protein that is abundant not only in bone tissue as a non-collagenous protein but is also ubiquitously expressed in non-calcified tissue. SPARC is located intracellularly and disruption of the Sparc gene has been reported to reduce bone formation and increase fat tissue; however, the mechanism by which SPARC inhibits adipogenesis remains unclear. The present study evaluated the intracellular function of SPARC in adipogenesis using the bone marrow stromal cell line ST2. When ST2 cells with low SPARC production were cloned, intrinsic activator protein-1 (AP-1) activity was markedly higher, mineralized nodule formation was significantly lower and lipid accumulation was significantly increased compared with in the parental ST2 cells. Forced expression of secreted SPARC with the signal peptide-coding sequences of wild-type Sparc or preprotrypsin in SPARC-low ST2 cells significantly reduced AP-1 transcription activity; however, these reductions were not observed in the absence of signal peptide sequences. Recombinant SPARC, produced using Brevibacillus brevis, specifically bound to c-Fos but not c-Jun and inhibited the binding of c-Fos/c-Jun to a TPA-response element sequence. These data suggested that SPARC was incorporated into the cells from the extracellular spaces and serves an intracellular role as a decoy counterpart for c-Fos, as well as being associated with osteoblastogenesis through the inhibition of adipogenesis. These findings may provide new insights into regenerative medicine.