PDGF receptor β is a potent regulator of mesenchymal stromal cell function
PDGF receptor β is a potent regulator of mesenchymal stromal cell function
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DOI：
10.1359/jbmr.080409
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发表时间：
2008-09-01
影响因子：
6.2
通讯作者：
Sasahara, Masakiyo
中科院分区：
文献类型：
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作者：
Tokunaga, Ayano;Oya, Takeshi;Sasahara, Masakiyo
骨髓间充质间质细胞（MSCs）在骨稳态中起着重要作用。尽管有报道称血小板衍生生长因子（PDGF）参与了MSCs的成骨分化，但其作用仍存在争议，PDGF在MSCs中的单克隆网络尚未明确。阐明PDGF介导MSC功能的潜在调控机制。我们通过Cre-loxP策略删除PDGF受体(PDGFR) β基因，并研究PDGF在MSCs成骨分化和骨折修复中的作用。在培养的MSCs中，检测PDGF-A、-B、-C和-D以及PDGFR α和β的mRNA表达。通过定量RT-PCR检测碱性磷酸酶（ALP）活性和ALP、骨钙素（OCN）、骨形态发生蛋白（BMP） 2、Runx2和osterix mRNA水平的升高，MSCs中PDGFR β的缺失降低了有丝分裂和迁移反应，增强了成骨分化。PDGF-BB抑制成骨分化，同时ALP活性和mRNA水平降低，但PDGF-AA抑制成骨分化，BMP2除外。PDGF-BB的这些作用通过MSCs中PDGFR β的缺失而消除，但PDGF-BB仍然抑制PDGFR β缺失MSCs中的骨表达。PDGFR β的缺失显著增加了骨折后编织骨与骨痂的比例。通过PDGF刺激和特异性PDGFR β基因缺失的联合分析，我们发现PDGFR β信号明显诱导增殖和迁移反应，但强烈抑制MSCs的成骨分化。PDGFR α对成骨分化的影响非常微弱。PDGFR β可以作为引导组织再生或骨组织工程的重要靶点。
Mesenchymal stromal cells (MSCs) in bone marrow are important for bone homeostasis. Although platelet-derived growth factor (PDGF) has been reported to be involved in osteogenic differentiation of MSCs, the role remains controversial and the network of PDGF silonaling for MSCs has not been clarified. To clarify the underlying regulatory mechanism of MSC functions mediated by PDGF., we deleted the PDGF receptor (PDGFR)beta gene by Cre-loxP strategy and examined the role of PDGF in osteogenic differentiation of MSCs and fracture repair. In cultured MSCs, the mRNA expression of PDGF-A, -B, -C, and -D as well as PDGFR alpha and beta was detected. Depletion of PDGFR beta in MSCs decreased the mitogenic and migratory responses and enhanced osteogenic differentiation as evaluated by increased alkaline phosphatase (ALP) activity and mRNA levels of ALP, osteocalcin (OCN), bone morphogenetic protein (BMP) 2, Runx2, and osterix in quantitative RT-PCR. PDGF-BB, but not PDGF-AA, inhibited osteogenic differentiation accompanied by decreased ALP activity and mRNA levels, except for BMP2. These effects of PDGF-BB were eliminated by depletion of PDGFR beta in MSCs except that PDGF-BB still suppressed osterix expression in PDGFR beta-depleted MSCs. Depletion of PDGFR beta significantly increased the ratio of woven bone to callus after fracture. From the combined analyses of PDGF stimulation and specific PDGFR beta gene deletion, we showed that PDGFR beta signaling distinctively induces proliferative and migratory responses but strongly inhibits osteogenic differentiation of MSCs. The effects of PDGFR alpha on the osteogenic differentiation were very subtle. PDGFR beta could represent an important target for guided tissue regeneration or tissue engineering of: bone.