Endocrine Abstracts

Genetic factors play an important role in osteoporosis. Several monogenic forms of osteoporosis have been recognized. The most common of these is osteogenesis imperfecta (OI) in which dominantly inherited mutations in the genes encoding type I collagen (COL1A1 and COL1A2) are responsible for approximately 90% of the cases. Several rare autosomal recessive forms of OI have also been described. In these the defects lie in proteins involved in posttranslational modification of type I collagen. Recent discoveries have further elucidated the genetic determinants of early-onset skeletal fragility and several forms not related to type I collagen have been identified. The discovery of LRP5 mutations in osteoporosis-pseudoglioma syndrome and in early-onset osteoporosis first indicated that the WNT signaling pathway plays an important role in bone mass accrual. Several other studies thereafter, including our discovery of WNT1 mutations in early-onset osteoporosis, have further highlighted the pathway’s significance in various disorders of low and high bone mass and provide evidence for the potential of WNT targeted therapies in osteoporosis treatment. The X-chromosomal osteoporosis caused by PLS3 gene mutations is another example of novel monogenic forms of osteoporosis that can be used to study cellular mechanisms leading to bone fragility. PLS3 osteoporosis affects mainly males and leads to severe progressive spinal osteoporosis; even females carrying the mutation may develop symptomatic osteoporosis. Our studies in patients with PLS3 deletions suggest that PLS3 plays a significant role in bone mineralization but the pathogenetic mechanisms are not fully understood. Several other monogenic forms of osteoporosis are under investigation. These highlight the complexity of molecular mechanisms governing normal