Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.

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ABSTRACT. We conducted a comprehensive study to investigate the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. Genotyping of seven gene polymorphisms was performed on a 384-well plate format on the Sequenom MassARRAY platform in 162 patients with osteosarcoma. We studied the correlation of the seven gene polymorphisms with response to chemotherapy and clinical outcome of patients. Individuals with the ABCB1 TT genotype had a higher probability of responding poorly to chemotherapy, indicated by an odds ratio (OR) of 2.64 (95%CI = 1.04-6.83). Similarly, the genotype of GSTP1 GG was significantly associated with improved responses to chemotherapy, indicated by an OR of 3.33 (95%CI = 1.26-8.99). The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter overall survival (OS). Our study found that two gene polymorphisms in two transporter genes and one Phase II metabolism enzymes are associated with response to chemotherapy and ABCB1 and GSTP1 and osteosarcoma survival OS in osteosarcoma patients, suggesting the potential of the two gene polymorphisms as prognostic biomarkers for osteosarcoma.

Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphingosine-1-phosphate (S1P) is a natural, bioactive sphingolipid that has been shown to play a major role in cardiovascular and immunological pathologies by regulating biological and cellular processes, including migration, differentiation, proliferation and survival. Recent studies also suggest a central role for S1P in bone diseases, including osteoporosis; however, the effects of S1P, particularly in bone metabolism, remain to be further elucidated. In this review, we summarize the available literature on the role of S1P in bone metabolism with a focus on osteoporosis. On the cellular level, S1P acts as an osteoclast-osteoblast coupling factor to promote osteoblast proliferation and bone formation. Moreover, the recruitment of osteoclast precursors to resorption sites is regulated by the interplay of S1P gradients and S1P receptor expression. From a clinical perspective, increasing evidence suggests that systemically elevated S1P blood levels may serve as an independent risk factor for osteoporosis-related fractures. Taken together, S1P signaling is a potential therapeutic target and may serve as a novel biomarker in patients with systemic bone disease.