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The activities of osteoclasts, which degrade bone, and osteoblasts, which form bone, are coordinated to maintain bone homeostasis. Zhao et al. (2006) now demonstrate bidirectional signaling between these two cell populations via the transmembrane ligand ephrinB2 expressed by osteoclasts and its receptor EphB4 expressed by osteoblasts. Such bidirectional signaling limits osteoclast activity while stimulating osteoblast differentiation.
Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTPeta), participates in developmental vascularization. A mutant allele, CD148(DeltaCyGFP), was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions.
Glomerular development proceeds through the spatially ordered and sequential recruitment, proliferation, assembly, and differentiation of endothelial, mesangial, and epithelial progenitors. The molecular determinants of cell-cell recognition and targeting in this process have yet to be defined. The Eph/ephrin family of membrane receptors and counter-receptors are critical participants of developmental vascular assembly in extrarenal sites. Renal expression patterns of ephrin-B2 and EphB4 were investigated using mice expressing beta-galactosidase under control of ephrin-B2 or EphB4 promoters. The earliest glomerular expression of ephrin-B2 was identified in a subset of differentiating comma-stage glomerular epithelial cells (podocyte progenitors) adjacent to the vascular cleft where endothelial progenitors are subsequently recruited. Epithelial ephrin-B2 expression was accompanied by expression in endothelial and mesangial cells as capillary assembly progressed. At or near completion of glomerular maturation, epithelial ephrin-B2 expression was extinguished, with persistence in glomerular endothelial cells. Throughout development, one of several ephrin-B2 receptors, EphB4, was persistently and exclusively expressed in endothelial cells of venous structures. The findings show sequential ephrin-B2 expression across glomerular lineages, first in a distinct subset of podocyte progenitors and subsequently in endothelial cells of the developing glomerulus. Given targeting functions for Eph/ephrin family proteins, the findings suggest that ephrin-B2 expression marks podocyte progenitors at the site of vascular cleft formation, where expression may establish an "address" to which endothelial and mesangial progenitors are recruited. Thus, the present results suggest that ephrin-B2 and EphB interactions play an important role in glomerular microvascular assembly.