Mbalaviele G, Nishimura R, Myoi A, Niewolna M, Reddy S V, Chen D, Feng J, Roodman D, Mundy G R, Yoneda T
Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Health Science Center, San Antonio, Texas 78284-7877, USA.
J Cell Biol. 1998 Jun 15;141(6):1467-76. doi: 10.1083/jcb.141.6.1467.
Osteoclasts are multinucleated cells of hemopoietic origin that are responsible for bone resorption during physiological bone remodeling and in a variety of bone diseases. Osteoclast development requires direct heterotypic cell-cell interactions of the hemopoietic osteoclast precursors with the neighboring osteoblast/stromal cells. However, the molecular mechanisms underlying these heterotypic interactions are poorly understood. We isolated cadherin-6 isoform, denoted cadherin-6/2 from a cDNA library of human osteoclast-like cells. The isolated cadherin-6/2 is 3,423 bp in size consisting of an open reading frame of 2,115 bp, which encodes 705 amino acids. This isoform lacks 85 amino acids between positions 333 and 418 and contains 9 different amino acids in the extracellular domain compared with the previously described cadherin-6. The human osteoclast-like cells also expressed another isoform denoted cadherin-6/1 together with the cadherin-6. Introduction of cadherin-6/2 into L-cells that showed no cell-cell contact caused evident morphological changes accompanied with tight cell-cell association, indicating the cadherin-6/2 we isolated here is functional. Moreover, expression of dominant-negative or antisense cadherin-6/2 construct in bone marrow-derived mouse stromal ST2 cells, which express only cadherin-6/2, markedly impaired their ability to support osteoclast formation in a mouse coculture model of osteoclastogenesis. Our results suggest that cadherin-6 may be a contributory molecule to the heterotypic interactions between the hemopoietic osteoclast cell lineage and osteoblast/bone marrow stromal cells required for the osteoclast differentiation. Since both osteoclasts and osteoblasts/bone marrow stromal cells are the primary cells controlling physiological bone remodeling, expression of cadherin-6 isoforms in these two cell types of different origin suggests a critical role of these molecules in the relationship of osteoclast precursors and cells of osteoblastic lineage within the bone microenvironment.
破骨细胞是造血来源的多核细胞，在生理性骨重塑过程以及多种骨疾病中负责骨吸收。破骨细胞的发育需要造血破骨细胞前体与相邻的成骨细胞/基质细胞之间直接的异型细胞间相互作用。然而，这些异型相互作用的分子机制仍知之甚少。我们从人破骨细胞样细胞的cDNA文库中分离出钙黏蛋白-6异构体，命名为钙黏蛋白-6/2。分离出的钙黏蛋白-6/2大小为3423 bp，包含一个2115 bp的开放阅读框，编码705个氨基酸。与先前描述的钙黏蛋白-6相比，该异构体在333位和418位之间缺少85个氨基酸，并且在细胞外结构域含有9个不同的氨基酸。人破骨细胞样细胞还与钙黏蛋白-6一起表达另一种异构体，命名为钙黏蛋白-6/1。将钙黏蛋白-6/2导入没有细胞间接触的L细胞中，导致明显的形态变化，并伴有紧密的细胞间结合，表明我们在此分离出的钙黏蛋白-6/2具有功能。此外，在仅表达钙黏蛋白-6/2的骨髓来源的小鼠基质ST2细胞中表达显性负性或反义钙黏蛋白-6/2构建体，在破骨细胞生成的小鼠共培养模型中显著损害了它们支持破骨细胞形成的能力。我们的结果表明，钙黏蛋白-6可能是破骨细胞分化所需的造血破骨细胞谱系与成骨细胞/骨髓基质细胞之间异型相互作用的一个促成分子。由于破骨细胞和成骨细胞/骨髓基质细胞都是控制生理性骨重塑的主要细胞，这两种不同来源的细胞类型中钙黏蛋白-6异构体的表达表明这些分子在骨微环境中破骨细胞前体与成骨细胞谱系细胞的关系中起关键作用。
