IntroductionAs a result of the aging process, the bone deteriorates in composition, structure and function, which predisposes to osteoporosis. Osteoporosis is defined as deterioration in bone mass and micro-architecture, with increasing risk to fragility fractures [Raisz and Rodan, 2003]. Owing to the close relationship between the aging process of bone and the pathogenesis of osteoporosis, research on the mechanisms of age-related bone loss has increased significantly in recent years involving a combination of basic, clinical, observational and translational studies.Bone is a dynamic organ that serves mechanical and homeostatic functions. It undergoes a continual self-regeneration process called remodeling. Remodeling removes old bone and replaces it with new bone. This regenerative process occurs in distinct areas of bone known as bone metabolic units (BMUs) [Riggs et al. 2002]. Within each BMU bone formation by osteoblasts and bone resorption by osteoclasts is coupled tightly in a delicate balance to maintain bone mass and strength to resist deformity. With aging this balance shifts in a negative direction, favoring greater bone resorption and less bone formation. This combination of bone mass deficiency and reduction in strength ultimately results in osteoporosis and fractures.Aging in combination with intrinsic and extrinsic factors accelerates the decline in bone mass that predisposes to fractures. Intrinsic factors include genetics, peak bone mass accrual in youth, alterations in cellular components, hormonal, biochemical and vasculature status. Extrinsic factors include nutrition, physical activity, comorbid medical conditions and drugs. In this article we review the mechanisms of age-related bone deterioration and their impact on the pathogenesis of osteoporosis. In addition, current and future therapeutic approaches focused on the correction of mechanisms associated with aging bone will also be outlined. Bone remodeling in aging boneRemodeling is continuous and coordinated cycle of removal of old bone by osteoclasts followed by the deposition of new bone by osteoblasts in response to micro damage and variable mechanical loadings. Bone remodeling is a continuous process throughout life. In the first three decades of life, bone turnover is coupled tightly to maintain a steady state between bone resorption and bone formation. Although there are variances in turnover rates, peak bone mass and size is achieved around the age of 15-20 years in women and later in men [Raisz and Seeman, 2001]. After this, long before sex steroids deficiency occurs, bone loss Aging and bone loss: new insights for the clinicianOddom Demontiero, Christopher Vidal and Gustavo Duque Abstract: It is well known that the underlying mechanisms of osteoporosis in older adults are different than those associated with estrogen deprivation. Age-related bone loss involves a gradual and progressive decline, which is also seen in men. Markedly increased bone resorption leads to the initial fall in bone mineral density. With increasing age, th...

The mechanisms involved in the anabolic effect of interferon gamma (IFNc) on bone have not been carefully examined. Using microarray expression analysis, we found that IFNc upregulates a set of genes associated with a tryptophan degradation pathway, known as the kynurenine pathway, in osteogenic differentiating human mesenchymal stem cells (hMSC). We, therefore, hypothesized that activation of the kynurenine pathway plays a role in osteoblastogenesis even in the absence of IFNc. Initially, we observed a strong increase in tryptophan degradation during osteoblastogenesis with and without IFNc in the media. We next blocked indoleamine 2,3-dioxygenase-1 (IDO1), the most important enzyme in the kynurenine pathway, using a siRNA and pharmacological approach and observed a strong inhibition of osteoblastogenesis with a concomitant decrease in osteogenic factors. We next examined the bone phenotype of Ido1 knockout (Ido1 2/2 ) mice. Compared to their wild-type littermates, Ido1 2/2 mice exhibited osteopenia associated with low osteoblast and high osteoclast numbers. Finally, we tested whether the end products of the kynurenine pathway have an osteogenic effect on hMSC. We identified that picolinic acid had a strong and dose-dependent osteogenic effect in vitro. In summary, we demonstrate that the activation of the kynurenine pathway plays an important role during the commitment of hMSC into the osteoblast lineage in vitro, and that this process can be accelerated by exogenous addition of IFNc. In addition, we found that mice lacking IDO1 activity are osteopenic. These data therefore support a new role for the kynurenine pathway and picolinic acid as essential regulators of osteoblastogenesis and as potential new targets of bone-forming cells in vivo. STEM CELLS 2015;33:111-121

Changes in the expression of lamin A/C, a fibrilar protein of the nuclear envelope, are associated with the cellular features of age-related bone loss. Reduced expression of lamin A/C inhibits osteoblastogenesis while facilitating adipogenic differentiation of mesenchymal stem cells (MSC) in vitro and in vivo. In this study we investigated the regulatory role that lamin A/C plays on the essential elements of the Wnt/β-catenin pathway, which are pivotal in MSC differentiation. Initially, we assessed the effect of lamin A/C gene (LMNA) overexpression on MSC differentiation while compared it to lamin A/C depleted MSC. Osteogenesis and gene expression of osteogenic factors were higher in LMNA-transfected MSC as compared to control. Conversely, adipogenesis and expression of adipogenic factors were significantly lower in LMNA transfected cells. Nuclear β-catenin was significantly higher (∼two fold) in MSC expressing higher levels of LMNA as compared to control with nuclear β-catenin levels being significantly lower (∼ -42%) in siRNA-treated MSC. Luciferase activity for β-catenin-mediated transcriptional activation was significantly higher in cells overexpressing LMNA. These data indicate that MSC overexpressing LMNA have higher osteogenic and lower adipogenic differentiation potential. In conclusion, our studies demonstrate that lamin A/C plays a significant role in the differentiation of both osteoblasts and adipocytes by regulating some of the elements of Wnt/β-catenin signaling during early MSC differentiation.

The interest in the relationship between fat and bone has increased steadily during recent years. Fat could have a lipotoxic effect on bone cells through the secretion of fatty acids. Palmitate is the most prevalent fatty acid secreted by adipocytes in vitro. Considering that palmitate has shown a high lipotoxic effect in other tissues, here we characterized the lipotoxic effect of palmitate on human osteoblasts (Obs). Initially we tested for changes in palmitoylation in this model. Subsequently we compared the capacity of Obs to differentiate and form bone nodules in the presence of palmitate. From a mechanistic approach, we assessed changes in nuclear activity of β-catenin and runt-related transcription factor 2 (Runx2)/phosphorylated mothers against decapentaplegic (Smad) complexes using Western blotting and confocal microscopy. Quantitative real-time PCR showed negative changes in gene expression of palmitoyltransferase genes. Furthermore, palmitate negatively affected differentiation and bone nodule formation and mineralization by Obs. Although the expression of β-catenin in palmitate-treated cells was not affected, there was a significant reduction in the transcriptional activities of both β-catenin and Runx2. Confocal microscopy showed that whereas Runx2 and Smad-4 and -5 complex formation was increased in bone morphogenetic protein-2-treated cells, palmitate had a negative effect on protein expression and colocalization of these factors. In summary, in this study we identified potential mechanisms of palmitate-induced lipotoxicity, which include changes in palmitoylation, defective mineralization, and significant alterations in the β-catenin and Runx2/Smad signaling pathways. Our evidence facilitates the understanding of the relationship between fat and bone and could allow the development of new potential therapies for osteoporosis in older persons.