Genetic regulation of bone mass and susceptibility to osteoporosis

Abstract

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

“…The current concept suggests that osteoporosis represents a continuum with multiple underlying mechanisms contributing to loss of bone mass and mineral density and overall microarchitectural deterioration of bones (Ferrari et al, 2004;Tasker et al, 2004;Bodine et al, 2005;Horowitz & Lorenzo, 2007;Perrini et al, 2010). These factors are causally related to increased risk of falls, contributing to high incidence of fragility fractures in osteoporotic patients (Raisz, 2005;Ralston & de Crombrugghe, 2006). Similar to the bone and muscle atrophy, also the skin is atrophic in mutant mice and intrinsically aged mice.…”

“…These pathological states share unique features and are all characterized by a loss of collagen type I, dysregulated fibroblast-matrix interactions and impaired fibroblast interactions with organ parenchyma, mainly with organ-specific epithelial cells and muscle (Wenk et al, 1999(Wenk et al, , 2004Krtolica & Campisi, 2002;Campisi, 2005;Labat-Robert & Robert, 2007;Treiber et al, 2009). A variety of genetic and environmental factors including increased concentration of ROS, mitochondrial dysfunction (Hiona & Leeuwenburgh, 2008), changes in autocrine, paracrine and endocrine release of hormones, growth factors (Perrini et al, 2010) and cytokines (Coppe et al, 2008) have been identified to contribute to skin aging, sarcopenia and osteoporosis in humans and rodents (Zofkova, 2003;Raisz, 2005;Ralston & de Crombrugghe, 2006;Hiona & Leeuwenburgh, 2008;Marzetti et al, 2009). Research on the regulation of connective tissue organization by enhanced release of ROS from mitochondria during fibroblast aging is a matter of increasing interest and relevance as it may provide ultimate clues for mechanisms underlying disruption of connective tissue homoeostasis in aging-related skin atrophy, sarcopenia and osteoporosis.…”

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening

“…Increased life expectancy in the Mexican population has contributed to a significant increase in the incidence and prevalence of this entity, and it has been estimated that 16 % of women aged above 50 years (1.3 million) are affected with this disease (Clark et al 2010). Both genetic and environmental factors are known to influence BMD variation, and heritability for this trait has been estimated between 50-80 % (Ralston and de Crombrugghe 2006).…”

Genetic profiling and individualized prognosis of fracture

“…Indeed, several studies during the past two decades have suggested a number of candidate genes for osteoporosis, (18) but the lack of independent replication has been a hindrance to progress of the field. In recent years, genome-wide association studies have been conducted, and a number of novel genes have been found to be associated with fracture risk.…”