Obesity, a growing health problem worldwide, has been associated with the metabolic syndrome, diabetes, cardiovascular disease, hypertension, and other chronic diseases. Recently, the obesity–cancer link has received much attention. Epidemiological studies have shown that obesity is also associated with increased risk of several cancer types, including colon, breast, endometrium, liver, kidney, esophagus, gastric, pancreatic, gallbladder, and leukemia, and can also lead to poorer treatment and increased cancer-related mortality. Biological mechanisms underlying the relationship between obesity and cancer are not well understood. They include modulation of energy balance and calorie restriction, growth factors, multiple signaling pathways and inflammatory processes. Key among the signaling pathways linking obesity and cancer is the PI3K/Akt/mTOR cascade, which is a target of many of the obesity-associated factors and regulates cell proliferation and survival. Understanding the molecular and cellular mechanisms of the obesity–cancer connection is important in developing potential therapeutics. The link between obesity with cancer underscores the recommendation to maintain a healthy body weight throughout life as one of the most important ways to protect against cancer.

Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.

Mutations of critical components of the Wnt pathway profoundly affect skeletal development and maintenance, probably via modulation of β-catenin signaling. We tested the hypothesis that β-catenin is involved in mesenchymal lineage allocation to osteogenic cells using a β-catenin mutant with constitutive transcriptional activity (ΔN151). Although this stable β-catenin had no effects by itself on osteogenic differentiation of multipotent embryonic cell lines, it synergized with bone morphogenetic protein-2 (BMP-2) resulting in dramatic stimulation of alkaline phosphatase activity, osteocalcin gene expression, and matrix mineralization. Likewise, ΔN151 and BMP-2 synergistically stimulated new bone formation after subperiosteal injection in mouse calvaria in vivo. Conversely, ΔN151 prevented adipogenic differentiation from pre-adipocytic or uncommitted mesenchymal cells in vitro. Intriguingly, the synergism with BMP-2 on gene transcription occurred without altering expression of Cbfa1/Runx2, suggesting actions independent or downstream of this osteoblastspecific transcription factor. Thus, β-catenin directs osteogenic lineage allocation by enhancing mesenchymal cell responsiveness to osteogenic factors, such as BMP-2, in part via Tcf/Lef dependent mechanisms. In vivo, this synergism leads to increased new bone formation. Keywords cell-cell adhesion; mesenchymal differentiation; bone formation; adipogenesisIn adult life, the skeleton is constantly remodeled to replace aging tissue and repair injuries by successive phases of osteoclast bone resorption and osteoblast mediated bone formation. Therefore, a continuous supply of bone forming cells is required to maintain bone homeostasis. Bone marrow mesenchymal stem cells are the source of osteoprogenitors in adult life, although these cells can also differentiate into adipocytes and myocytes in the presence of appropriate stimuli [Pittenger et al., 1999]. Lineage allocation of mesenchymal stem cells to either osteogenic or adipogenic cells must be kept in a critical balance, and shifts that may favor one lineage over the other may have important consequences for an individual's ability to produce sufficient numbers of bone forming cells. An osteogenic to adipogenic shift may explain the pathogenesis of age-dependent bone loss, which is associated with a reduced potential of bone marrow to produce osteogenic cells in the face of an increased number of adipocytes [Jilka et al., 1996;Gimble and Nuttall, 2004]. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe osteogenic differentiation program is under the control of hormonal and local factors converging onto a finite number of transcriptional regulators that ultimately determine the fate of cells committing to the osteogenic lineage [Karsenty and Wagner, 2002]. An emerging body of work demonstrates that the Wnt signaling system is one of the most important local regulators of bone formation, presumably via activation of the β-catenin signaling system. Wnts are a family of secreted protei...

Loss-of-function mutations of gap junction proteins, connexins, represent a mechanism of disease in a variety of tissues. We have shown that recessive (gene deletion) or dominant (connexin45 overexpression) disruption of connexin43 function results in osteoblast dysfunction and abnormal expression of osteoblast genes, including down-regulation of osteocalcin transcription. To elucidate the molecular mechanisms of gap junction-sensitive transcriptional regulation, we systematically analyzed the rat osteocalcin promoter for sensitivity to gap junctional intercellular communication. We identified an Sp1/Sp3 containing complex that assembles on a minimal element in the -70 to -57 region of the osteocalcin promoter in a gap junction-dependent manner. This CT-rich connexin-response element is necessary and sufficient to confer gap junction sensitivity to the osteocalcin proximal promoter. Repression of osteocalcin transcription occurs as a result of displacement of the stimulatory Sp1 by the inhibitory Sp3 on the promoter when gap junctional communication is perturbed. Modulation of Sp1/Sp3 recruitment also occurs on the collagen Ialpha1 promoter and translates into gap junction-sensitive transcriptional control of collagen Ialpha1 gene expression. Thus, regulation of Sp1/Sp3 recruitment to the promoter may represent a potential general mechanism for transcriptional control of target genes by signals passing through gap junctions.

Gap junctions play a critical role in the coordinated function and activity of nearly all of the skeletal cells. This is not surprising, given the elaborate orchestration of skeletal patterning, bone modeling and subsequent remodeling, as well as the mechanical stresses, strains and adaptive responses that the skeleton must accommodate. Much remains to be learned regarding the role of gap junctions and hemichannels in these processes. A common theme is that without connexins none of the cells of bone function properly. Thus, connexins play an important role in skeletal form and function.