Professor Claes Ohlsson
Professor Hans Carlsten
Professor Dan Mellström
Professor Olle Isaksson
Centre for Bone and Arthritis Research
Osteoporosis, a skeletal disorder characterized by compromised bone strength, increases the risk of fracture. Osteoporosis is becoming more prevalent in the Western world, and the highest prevalence is found in Sweden and Norway. Bone fractures often result from reduced bone mass due to (1) low peak bone mass caused by failure to achieve normal bone mass during childhood or adolescence or (2) accelerated age-dependent bone loss. SS are of major importance in the regulation of both processes. The long-term aim of this module is to understand the mechanisms by which SS exerts these regulatory effects. A better understanding of effects of and mechanisms of action for SS in the skeleton may result in new treatment strategies for osteoporosis.
To characterize the primary target tissue/cells for SS in the regulation of bone mass, Drs. Ohlsson, Isaksson and Carlsten will develop and analyze the skeletal phenotype of mouse models in which the cre-LoxP systems is used to specifically inactivate the ERa, ERb, AR in osteoblasts, chondrocytes, osteoclasts, and T-lymphocytes and in the hypothalamus.
The effects of estrogens are mainly mediated by the ERa and ERb. However, recent in vitro data indicate that the membrane-bound GPR30 also is a functional ER (mER). To investigate in vivo the physiological function of this putative seven-transmembrane-spanning ER, they will collaborate with Professor Björn Olde (Lund University) to characterize the skeletal phenotype and other phenotypes of the recently developed GPR30 inactivated mouse model.
Besides SS receptors, enzymes and binding proteins that regulate tissue levels of active SS might be important targets for novel specific treatments of osteoporosis. Researchers in this module will investigate the skeletal phenotype of several different mouse models with altered local tissue levels of active SS, including catechol-O-methyltransferase inactivated mice, sex hormone-binding globulin transgenic mice, 5-alpha reductase type 1 and type 2 inactivated mice, and mice overexpressing aromatase specifically in bone or muscle.
Previous studies of the genetic and environmental determinants of peak bone mass were limited by the use of two-dimensional dual X-ray absorptiometry (DXA) for bone analyses. For the genetic analyses of peak bone mass, researchers in this module have access to two ongoing longitudinal cohorts in which both DXA and a much more informative and specific three-dimensional computer tomography (CT) technique are being used to analyze skeletal parameters in 1068 men followed from 18 years of age (GOOD) and 250 girls followed from 10 years of age (CALEX). For studies of bone mineral density and fractures in the elderly, the researchers have access to a cohort of 3000 men followed from 70 years of age (MrOS-Sweden) and a cohort of 1000 women followed from 60 years of age (Nordos). These subjects are being followed longitudinally by repeated DXA and CT analyses, and verified fractures are being recorded.
Genetic analyses of these cohorts will include haplotype analyses of 25 major SS-related genes. Genes involved in the synthesis, action, and degradation of SS will be investigated. The genotypes will then be associated with skeletal phenotypes in the different cohorts. Gene-gene and gene-environmental interactions will be evaluated in detail.
Epigenetic mechanisms such as DNA methylation might also contribute to variation in bone mass. Recent studies of monozygotic twins indicate that environmental factors influence DNA methylation and thereby gene transcription in adulthood. The researchers will characterize environmental factors associated with the degree of DNA methylation of ERa, ERb, and the AR in cells involved in bone metabolism. They will also determine if the degree of DNA methylation of these genes is associated with the different skeletal phenotypes.
Gröna Stråket 8, 413 45 Göteborg
Endokrinologen, Sahlgrenska Sjukhuset
+46 31 3422873
Guldhedsgatan 10A, 413 45 Göteborg
Department of Rheumatology and Inflammation Research
+46 31 3424017