Gevers Evelien F, Loveridge Nigel, Robinson Iain C A F
Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
Endocrinology. 2002 Oct;143(10):4065-73. doi: 10.1210/en.2002-220428.
Bone marrow (BM) contains numerous adipocytes. These share a common precursor with osteoblasts and chondrocytes, but their function is unknown. It is unclear what regulates the differentiation of these three different cell types, though their subsequent metabolic activity is under hormonal regulation. GH and estrogen stimulate bone growth and mineralization, by direct effects on chondrocytes and osteoblasts. GH also stimulates lipolysis in subcutaneous and visceral adipocytes. However, adipocytes in BM have largely been ignored as potential targets for GH or estrogen action. We have addressed this by measuring BM adipocyte number, perimeter and area as well as bone area and osteoblast activity in GH-deficient dwarf (dw/dw), normal, or ovariectomized (Ovx) rats, with or without GH, IGF-1, PTH, or estrogen treatment or high fat feeding. Marrow adipocyte numbers were increased 5-fold (P < 0.001) in dw/dw rats, and cell size was also increased by 20%. These values returned toward normal in dw/dw rats given GH but not when given IGF-1. Cancellous bone area and osteoblast number were significantly (P < 0.005) lower in dw/dw rats, though alkaline phosphatase (ALP) activity in individual osteoblasts was unchanged. GH treatment increased % osteoblast covered bone surface without affecting individual cell ALP activity. Ovariectomy in normal or dw/dw rats had no affect on marrow adipocyte number nor size, although estrogen treatment in ovariectomized (Ovx) normal rats did increase adipocyte number. Ovx decreased tibial cancellous bone area in normal rats (64%; P < 0.05) and decreased osteoblast ALP-activity (P < 0.01) but did not affect the percentage of osteoblast-covered bone surface. Estrogen replacement reversed these changes. While treatment with PTH by continuous sc infusion decreased cancellous bone (P < 0.05) and high fat feeding increased the size of BM adipocytes (P < 0.01), they did not affect BM adipocyte number. These results suggest that GH has a specific action on BM adipocytes that is not simply due to altered bone or fat metabolism. We conclude that the marrow adipocyte lineage is an important and specific target for GH action. The inverse relationship between adipocyte number and osteoblast covered bone surface, together with the well-known effects of GH on epiphysial chondrocytes leads us to propose that GH plays two important roles on cells of all three lineages. During differentiation, it regulates the numbers of each cell type that are maintained from the common precursor lineage. Subsequently it has cell-specific effects on the metabolic activities of the differentiated cells. In the case of marrow adipocytes, GH-dependent lipolysis could provide an important hormonally regulated local high energy source in bone.
骨髓（BM）中含有大量脂肪细胞。这些脂肪细胞与成骨细胞和软骨细胞有着共同的前体细胞，但它们的功能尚不清楚。虽然这三种不同细胞类型的后续代谢活动受激素调节，但不清楚是什么调节它们的分化。生长激素（GH）和雌激素通过直接作用于软骨细胞和成骨细胞来刺激骨骼生长和矿化。GH还能刺激皮下和内脏脂肪细胞的脂肪分解。然而，骨髓中的脂肪细胞在很大程度上被忽视了，未被视为GH或雌激素作用的潜在靶点。我们通过测量生长激素缺乏型侏儒（dw/dw）大鼠、正常大鼠或去卵巢（Ovx）大鼠在接受或未接受GH、胰岛素样生长因子-1（IGF-1）、甲状旁腺激素（PTH）或雌激素治疗，以及高脂喂养情况下的骨髓脂肪细胞数量、周长和面积，以及骨面积和成骨细胞活性，来解决这个问题。dw/dw大鼠的骨髓脂肪细胞数量增加了5倍（P < 0.001），细胞大小也增加了20%。给予GH的dw/dw大鼠这些数值恢复到接近正常水平，但给予IGF-1时则未恢复。dw/dw大鼠的松质骨面积和成骨细胞数量显著降低（P < 0.005），尽管单个成骨细胞中的碱性磷酸酶（ALP）活性未变。GH治疗增加了成骨细胞覆盖的骨表面百分比，而不影响单个细胞的ALP活性。正常或dw/dw大鼠去卵巢对骨髓脂肪细胞数量和大小均无影响，尽管去卵巢（Ovx）正常大鼠接受雌激素治疗确实增加了脂肪细胞数量。去卵巢使正常大鼠的胫骨松质骨面积减少（64%；P < 0.05），并降低了成骨细胞的ALP活性（P < 0.01），但不影响成骨细胞覆盖的骨表面百分比。雌激素替代可逆转这些变化。虽然持续皮下输注PTH治疗可减少松质骨（P < 0.05），高脂喂养可增加骨髓脂肪细胞大小（P < 0.01），但它们均不影响骨髓脂肪细胞数量。这些结果表明，GH对骨髓脂肪细胞具有特定作用，而不仅仅是由于骨骼或脂肪代谢的改变。我们得出结论，骨髓脂肪细胞谱系是GH作用的一个重要且特定的靶点。脂肪细胞数量与成骨细胞覆盖的骨表面之间的负相关关系，以及GH对骨骺软骨细胞的众所周知的作用，使我们提出GH在所有这三种谱系的细胞上发挥两个重要作用。在分化过程中，它调节从共同前体细胞谱系中维持的每种细胞类型的数量。随后，它对分化细胞的代谢活动具有细胞特异性作用。就骨髓脂肪细胞而言，GH依赖性脂肪分解可为骨骼中一种重要的受激素调节的局部高能源。
