Immortalized human chondrocytes were established by transfection of primary cultures of juvenile costal chondrocytes with vectors encoding simian virus 40 large T antigen and selection in suspension culture over agarose. Stable cell lines were generated that exhibited chondrocyte morphology, continuous proliferative capacity (> 80 passages) in monolayer culture in serum-containing medium, and expression of mRNAs encoding chondrocyte-specific collagens II, IX, and XI and proteoglycans in an insulin-containing serum substitute. They did not express type X collagen or versican mRNA. These cells synthesized and secreted extracellular matrix molecules that were reactive with monoclonal antibodies against type II collagen, large proteoglycan (PG-H, aggrecan), and chondroitin-4-and chondroitin-6-sulfate. Interleukin-1,8 (IL-1p) decreased the levels of type II collagen mRNA and increased the levels of mRNAs for collagenase, stromelysin, and immediate early genes (egr-1, c-fos, c-jun, and jun-B). These cell lines also expressed reporter gene constructs containing regulatory sequences (-577/+3,428 bp) of the type II collagen gene (COL2A1) in transient transfection experiments, and IL-1p8 suppressed this expression by 50-80%. These results show that immortalized human chondrocytes displaying cartilage-specific modulation by IL-1,3 can be used as a model for studying normal and pathological repair mechanisms. (J. Clin. Invest. 1994. 94:2307-2316

During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. Here, using extensive analysis of pro-fibrotic cells during mouse skin wound healing, fibrosis and aging; we identify distinct subpopulations of myofibroblasts, including cells identified as adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that AP proliferation, and not other myofibroblasts, is activated by CD301b-expressing macrophages through IGF1 and PDGFC. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding.

Purpose: Patients with neurofibromatosis 1 (NF1) are at increased risk for a variety of cardiovascular disorders, but the natural history and pathogenesis of these abnormalities are poorly understood. Methods: The National Neurofibromatosis Foundation convened an expert task force to review current knowledge about cardiovascular manifestations of NF1 and to make recommendations regarding clinical management and research priorities related to these features of the disease. Results: This report summarizes the NF1 Cardiovascular Task Force's current understanding of vasculopathy, hypertension, and congenital heart defects that occur in association with Key Words: neurofibromatosis 1, vasculopathy, hypertension, congenital heart defects Neurofibromatosis 1 (NF1), an autosomal dominant disease, is one of the most common mendelian disorders. 1 It is characterized by extremely variable expressivity, but most patients have café-au-lait spots, intertriginous freckling, dermal and plexiform neurofibromas, and learning disabilities. 2 People with NF1 may also develop cardiac and vascular disease, but the frequency, natural history, and pathogenesis of these abnormalities are uncertain. The National Neurofibromatosis Foundation convened an expert panel, the NF1 Cardiovascular Task Force, to review current knowledge about the cardiovascular manifestations of NF1 and to make recommendations regarding clinical management and research priorities. This is the report of that Task Force.Neurofibromas, the characteristic tumors of NF1, can develop within the heart, obstruct blood flow in the heart or major vessels by compression or invasion, or erode a vessel and cause hemorrhage. Fortunately, these are rare complications. This report will concentrate on the three most common cardiovascular manifestations of NF1, viz., vasculopathy, hypertension, and congenital heart defects.People with NF1 constitute a substantial fraction of all patients with dysplastic renal artery stenosis, 3 early-onset cerebrovascular disease, 4 or pheochromocytomas, 5 and cardiovascular disease is a frequent cause of premature death in individuals with NF1. Sørensen and associates 6 found that myocardial infarction and cerebrovascular accidents often occurred at a younger than expected age among NF1 patients. Zöller et al. 7 reported that cardiovascular disease, hemorrhage, and embolism were frequent causes of death in 70 adult NF1 patients who were followed for 12 years. Hypertension was significantly associated with mortality, and the mean age at death among the NF1 patients was approximately 14 years younger than expected. The median age of death reported on death certificates of 3,253 individuals with probable NF1 was approximately 15 years less than expected in another study. 8 Diagnoses suggestive of NF1 vasculopathy were listed 7.2 times more often than expected among NF1 patients Ͻ 30 years old and 2.2 times more often than expected among those who were 30 to 40 years old at the time of death. NF1 VASCULOPATHY Epidemiology and clinical featuresNF1 c...

The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change likely requires a change in the balance of angiogenic stimulators and angiogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angiogenic switching is accompanied by up-regulation of vascular endothelial growth factor and matrix metalloproteinase (MMP) bioactivity and downregulation of tissue inhibitor of MMP. Furthermore, we show that inhibition of phosphatidylinositol-3-kinase leads to partial inhibition of tumor angiogenesis, thus demonstrating that activated H-ras activates tumor angiogenesis through two distinct pathways. Finally, we show evidence for two forms of tumor dormancy.