Genetic research in osteoporosis: Where are we? Where should we go next?

Fractures resulting from low bone mass and excessive skeletal fragility (osteoporosis) are common worldwide both in males and females, particularly in later years of life. Both fractures, and the most important predictor of fractures, bone mass, are now known to be strongly heritable. This fact, plus the current growth in genetic science, has led to a surge of genetic research in osteoporosis, mostly in the search for genes and their polymorphisms that are responsible for variation in bone mass. Finding the genetic basis underlying variation in bone mass will lead us to deeper understanding of the biology of bone mass accumulation, maintenance and adaptation to load. This, plus finding the genetic basis for overall variation in fracture risk per se, will facilitate the development of interventions, both pharmaceutical and non-pharmaceutical, to prevent and/or treat osteoporosis successfully. This research has produced a rather large number of gene loci that seem to influence bone mass. The challenge now is to refine the statistical genetics and the phenotypes involved so that we can confidently identify those gene loci that truly influence bone mass, and to find ways to study the genetic basis for the most direct disease outcome of interest, fracture.     

Leptin in farm animals: where are we and where can we go?

Fat affects meat quality, value and production efficiency as well as providing energy reserves for pregnancy and lactation in farm livestock. Leptin, the adipocyte product of the obese (ob) gene, was quickly seen as a predictor of body fat content in animals approaching slaughter and an aid to assessing reproductive readiness in females. Its participation in inflammation and immune responses that help animals survive infection and trauma has clear additional relevance to meat and milk production. Furthermore, almost a decade of discoveries of nucleotide polymorphisms in the leptin and leptin receptor genes has suggested useful applications relating to feed intake regulation, the efficiency of feed use, the composition of growth, the timing of puberty, mammogenesis and mammary gland function and fertility in cattle, pigs and poultry. The current review attempts to summarise where research has taken us in each of these aspects and speculates on where future research might lead.     

Genetic design automation: engineering fantasy or scientific renewal?

The aim of synthetic biology is to make genetic systems more amenable to engineering, which has naturally led to the development of computer-aided design (CAD) tools. Experimentalists still primarily rely on project-specific ad hoc workflows instead of domain-specific tools, which suggests that CAD tools are lagging behind the front line of the field. Here, we discuss the scientific hurdles that have limited the productivity gains anticipated from existing tools. We argue that the real value of efforts to develop CAD tools is the formalization of genetic design rules that determine the complex relationships between genotype and phenotype.     

How do in vitro reconstituted actin-based motility assays provide insight into in vivo behavior?

Recent live cell image analysis of actin dynamics in lamellipodia of motile cells has shown that regulated treadmilling, which supports actin-based propulsion of functionalized particles in biomimetic reconstituted motility assays, is also responsible for lamellipodia extension. In both cases, filaments are created by branching with Arp2/3 complex only at the membrane or particle surface, grow transiently and are capped; ADF/cofilin enhances the treadmilling but does not sever filaments in the body of the meshwork. Differences between the cellular and biomimetic systems suggest that additional regulatory mechanisms take place in lamellipodia.     

Measuring bone mass in children: can we really do it?

Bone densitometry is used to assess skeletal health in clinical and research settings, with the goal of achieving reproducible measurements of bone mass that help to identify individuals predisposed to fracture. The search is now on for better methods of capturing additional factors that contribute to bone strength, including bone size, geometry, microarchitecture, and turnover rates. This has proved particularly challenging in growing children, whose bones continually change in size, shape, and mass. Dual energy X-ray absorptiometry is the preferred method for measuring bone mass in children, but the technique has several limitations, and interpreting the findings can be problematic. Peripheral quantitative computed tomography is a promising method for assessing bone mass and other indices correlating with bone strength, but a lack of precision and paediatric norms currently restricts its clinical utility. Although bone mineral density is predictive of future fracture risk in adults, the evidence in children is less conclusive, and a diagnosis of osteoporosis in a child should not be made on densitometric findings alone. Developing a clearer understanding of how measures of bone mass and strength correlate with bone fracture in children will help target preventive strategies for those in greatest need.     

Lipids in cell biology: how can we understand them better?

Lipids are a major class of biological molecules and play many key roles in different processes. The diversity of lipids is on the same order of magnitude as that of proteins: cells express tens of thousands of different lipids and hundreds of proteins to regulate their metabolism and transport. Despite their clear importance and essential functions, lipids have not been as well studied as proteins. We discuss here some of the reasons why it has been challenging to study lipids and outline technological developments that are allowing us to begin lifting lipids out of their “Cinderella” status. We focus on recent advances in lipid identification, visualization, and investigation of their biophysics and perturbations and suggest that the field has sufficiently advanced to encourage broader investigation into these intriguing molecules.Lipids are fundamental building blocks of all cells and play many important and varied roles. They are key components of the plasma membrane and other cellular compartments, including the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, and trafficking vesicles such as endosomes and lysosomes. The lipid composition of different organelles, cell types, and ultimately tissues can vary substantially, suggesting that different lipids are required for different functions (Saghatelian et al., 2006 ; Klose et al., 2013 ). Mammalian cells express tens of thousands of different lipid species and use hundreds of proteins to synthesize, metabolize, and transport them. Although the complexity and diversity of lipids approach those of proteins, we have a much poorer understanding of their functions, making lipids in many ways the “Cinderellas” of cell biology. We discuss here recent advances, and challenges, in investigating how these molecules contribute to the many biological processes in which they participate.Like proteins, lipids can have structural (e.g., by stabilizing different membrane curvatures) or signaling roles. Posttranslational lipidation of proteins (e.g., palmitoylation or farnesylation) and carbohydrate-linked lipids (glycolipids) are also important examples of cellular lipid pools. It is clear that higher-order organization is key to most lipid functions, and they are believed to assemble into signaling platforms that contain both lipids and proteins (Kusumi et al., 2012 ). Some lipid microdomains are termed lipid rafts, and much ongoing effort is being focused on defining their parameters (Simons and Sampaio, 2011 ; Suzuki et al., 2012 ; Klotzsch and Schutz, 2013 ). Because of this focus on lipid rafts, we have a better understanding of the properties of proposed raft lipids (e.g., sphingomyelins and cholesterol) than of many other lipid species. Much of what we know about lipids has come from studying synthetic membranes with specific lipid compositions. Although model membranes usually consist of very few (<10) lipid species, they have been useful for understanding the biophysical properties of lipids. At the other end of the spectrum, lipids have been implicated in various diseases, with cholesterol metabolism being a prominent example. We are now getting to a point at which we can address the roles of lipids in the middle of the spectrum—in cells.     

High-resolution MRI: in vivo histology?

For centuries scientists have been fascinated with the question of how the brain works. Investigators have looked at both where different functions are localized and how the anatomical microstructure varies across the brain surface. Here we discuss how advances in magnetic resonance imaging (MRI) have allowed in vivo visualization of the fine structure of the brain that was previously only visible in post-mortem brains. We present data showing the correspondence between definitions of the primary visual cortex defined anatomically using very high-resolution MRI and functionally using functional MRI. We consider how this technology can be applied to allow the investigation of brains that differ from normal, and what this ever-evolving technology may be able to reveal about in vivo brain structure in the next few years.     

Estrogen and memory in women: how can we reconcile the findings?

Although several randomized controlled trials (RCTS) of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the RCT, the Women's Health Initiative Memory Study (WHIMS), have reported inconsistent information with regard to the relationship between estrogen and aspects of cognitive function. Although numerous reasons could be offered to explain these discrepancies in research findings, recent evidence from rodent, nonhuman primate, and human studies consistently suggests that one possibility may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy (OVX), provides a window of opportunity for the preservation of memory in females whereas the administration of the hormone following a considerable delay in time after OVX has little or no beneficial effect on cognition. Considering the evidence that, in several organ systems, heightened disease risks accrue to a longer duration of estrogen deprivation in women, it would seem important to determine whether this is also true for brain structure and function in order to protect the quality of life for the considerable number of women who undergo a surgical menopause before their natural menopause had occurred.     

MAPK signalling in rheumatoid joint destruction: can we unravel the puzzle?

Mitogen-activated protein kinases (MAPKs) have been associated with the pathogenesis of rheumatoid arthritis (RA), but the individual contributions of the three MAPK family members are incompletely understood. Although previous data have established a role for c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK) in different animal models of arthritis, most recent data indicate that the stable activation of p38 MAPK and in part of ERK significantly contributes to destructive arthritis in mice transgenic for human tumour necrosis factor-alpha. These data highlight the complexity of MAPK signalling in arthritis and provide a basis for the design of novel strategies to treat human RA.     

Malaria in pregnancy and the endemicity spectrum: what can we learn?

The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.     

Sugarcane improvement: how far can we go?

In recent years, efforts to improve sugarcane have focused on the development of biotechnology for this crop. It has become clear that sugarcane lacks tools for the biotechnological route of improvement and that the initial efforts in sequencing ESTs had limited impact for breeding. Until recently, the models used by breeders in statistical genetics approaches have been developed for diploid organisms, which are not ideal for a polyploid genome such as that of sugarcane. Breeding programs are dealing with decreasing yield gains. The contribution of multiple alleles to complex traits such as yield is a basic question underlining the breeding efforts that could only be addressed by the development of specific tools for this grass. However, functional genomics has progressed and gene expression profiling is leading to the definition of gene networks. The sequencing of the sugarcane genome, which is underway, will greatly contribute to numerous aspects of research on grasses. We expect that both the transgenic and the marker-assisted route for sugarcane improvement will contribute to increased sugar, stress tolerance, and higher yield and that the industry for years to come will be able to rely on sugarcane as the most productive energy crop.