Chen D, Ji X, Harris M A, Feng J Q, Karsenty G, Celeste A J, Rosen V, Mundy G R, Harris S E
Department of Medicine, Division of Endocrinology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284, USA.
J Cell Biol. 1998 Jul 13;142(1):295-305. doi: 10.1083/jcb.142.1.295.
Cumulative evidence indicates that osteoblasts and adipocytes share a common mesenchymal precursor and that bone morphogenetic proteins (BMPs) can induce both osteoblast and adipocyte differentiation of this precursor. In the present study, we investigated the roles of BMP receptors in differentiation along these separate lineages using a well-characterized clonal cell line, 2T3, derived from the mouse calvariae. BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions. To test the specific roles of the type IA and IB BMP receptor components, truncated and constitutively active type IA and IB BMP receptor cDNAs were stably expressed in these cells. Overexpression of truncated type IB BMP receptor (trBMPR-IB) in 2T3 cells completely blocked BMP-2-induced osteoblast differentiation and mineralized bone matrix formation. Expression of trBMPR-IB also blocked mRNA expression of the osteoblast specific transcription factor, Osf2/ Cbfa1, and the osteoblast differentiation-related genes, alkaline phosphatase (ALP) and osteocalcin (OC). BMP-2-induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB. Expression of a constitutively active BMPR-IB (caBMPR-IB) induced formation of mineralized bone matrix by 2T3 cells without addition of BMP-2. In contrast, overexpression of trBMPR-IA blocked adipocyte differentiation and expression of caBMPR-IA induced adipocyte formation in 2T3 cells. Expression of the adipocyte differentiation-related genes, adipsin and PPARgamma, correlated with the distinct phenotypic changes found after overexpression of the appropriate mutant receptors. These results demonstrate that type IB and IA BMP receptors transmit different signals to bone-derived mesenchymal progenitors and play critical roles in both the specification and differentiation of osteoblasts and adipocytes.
累积证据表明，成骨细胞和脂肪细胞拥有共同的间充质前体细胞，并且骨形态发生蛋白（BMPs）能够诱导该前体细胞向成骨细胞和脂肪细胞分化。在本研究中，我们使用源自小鼠颅骨的特征明确的克隆细胞系2T3，研究了BMP受体在这些不同谱系分化过程中的作用。根据培养条件，BMP-2可诱导2T3细胞分化为成熟的成骨细胞或脂肪细胞。为了测试IA型和IB型BMP受体组分的特定作用，截短的和组成型激活的IA型和IB型BMP受体cDNA在这些细胞中稳定表达。在2T3细胞中过表达截短的IB型BMP受体（trBMPR-IB）完全阻断了BMP-2诱导的成骨细胞分化和矿化骨基质形成。trBMPR-IB的表达还阻断了成骨细胞特异性转录因子Osf2/Cbfa1以及成骨细胞分化相关基因碱性磷酸酶（ALP）和骨钙素（OC）的mRNA表达。通过将野生型（wt）BMPR-IB转染到含有trBMPR-IB的2T3克隆中，可以挽救BMP-2诱导的ALP活性。组成型激活的BMPR-IB（caBMPR-IB）的表达在不添加BMP-2的情况下诱导2T3细胞形成矿化骨基质。相反，trBMPR-IA的过表达阻断了脂肪细胞分化，而caBMPR-IA的表达在2T3细胞中诱导了脂肪细胞形成。脂肪细胞分化相关基因脂肪酶和PPARγ的表达与过表达相应突变受体后发现的明显表型变化相关。这些结果表明，IB型和IA型BMP受体向骨源性间充质祖细胞传递不同的信号，并在成骨细胞和脂肪细胞的特化及分化中起关键作用。
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