Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations1. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms2. Here, we show that excessive transforming growth factor-beta (TGFβ) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) OI mouse models. In the skeleton, we find higher expression of TGFβ target genes, ratio of pSmad2/Smad2 protein, and in vivo Smad2 reporter activity. Anti-TGFβ treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI, and improves the lung abnormalities in Crtap−/− mice. Moreover, type I collagen of Crtap−/− mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGFβ activity3–4. Hence, altered TGFβ matrix-cell signaling is a primary mechanism in the pathogenesis of OI, and could be a promising target for the treatment of OI.

Mesenchymal stem cells (MSCs) can differentiate into several lineages during development and also contribute to tissue homeostasis and regeneration, although the requirements for both may be distinct. MSC lineage commitment and progression in differentiation are regulated by members of the transforming growth factor-β (TGF-β) family. This review focuses on the roles of TGF-β family signaling in mesenchymal lineage commitment and differentiation into osteoblasts, chondrocytes, myoblasts, adipocytes, and tenocytes. We summarize the reported findings of cell culture studies, animal models, and interactions with other signaling pathways and highlight how aberrations in TGF-β family signaling can drive human disease by affecting mesenchymal differentiation.

Objective MicroRNA reflect physiologic and pathologic processes and may be used as biomarkers of concurrent pathophysiologic events in complex settings such as autoimmune diseases. We generated microRNA microarray profiles from the minor salivary glands of control subjects without Sjögren's syndrome (SS) and patients with SS who had low-grade or high-grade inflammation and impaired or normal saliva production, to identify microRNA patterns specific to salivary gland inflammation or dysfunction. Methods MicroRNA expression profiles were generated by Agilent microRNA arrays. We developed a novel method for data normalization by identifying housekeeping microRNA. MicroRNA profiles were compared by unsupervised mathematical methods to test how well they distinguish between control subjects and various subsets of patients with SS. Several bioinformatics methods were used to predict the messenger RNA targets of the differentially expressed microRNA. Results MicroRNA expression patterns accurately distinguished salivary glands from control subjects and patients with SS who had low-degree or high-degree inflammation. Using real-time quantitative polymerase chain reaction, we validated 2 microRNA as markers of inflammation in an independent cohort. Comparing microRNA from patients with preserved or low salivary flow identified a set of differentially expressed microRNA, most of which were up-regulated in the group with decreased salivary gland function, suggesting that the targets of microRNA may have a protective effect on epithelial cells. The predicted biologic targets of microRNA associated with inflammation or salivary gland dysfunction identified both overlapping and distinct biologic pathways and processes. Conclusion Distinct microRNA expression patterns are associated with salivary gland inflammation and dysfunction in patients with SS, and microRNA represent a novel group of potential biomarkers.

Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days.Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 Ag/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m 2 and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m 2 of 5-AZA in combination with valproic acid. Doselimiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m 2 of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m 2 for 5-AZA in patients with advanced malignancies.

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.