MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

Abstract

Throughout life, bone is continuously remodelled to be able to fulfil its multiple functions. The importance of strictly regulating the bone remodelling process, which is defined by the sequential actions of osteoclasts and osteoblasts, is shown by a variety of disorders with abnormalities in bone mass and strength. The best known and most common example of such a disorder is osteoporosis, which is marked by a decreased bone mass and strength that consequently results in an increased fracture risk. As osteoporosis is a serious health problem, a large number of studies focus on elucidating the aetiology of the disease as well as on the identification of novel therapeutic targets for the treatment of osteoporotic patients. These studies have demonstrated that a large amount of variation in bone mass and strength is often influenced by genetic variation in genes encoding important regulators of bone homeostasis. Throughout the years, studies into the genetic causes of osteoporosis as well as several rare monogenic disorders with abnormal high or low bone mass and strength have largely increased the knowledge on regulatory pathways important for bone resorption and formation. This review gives an overview of genes and pathways that are important for the regulation of bone formation and that are identified through their involvement in monogenic and complex disorders with abnormal bone mass. Furthermore, novel bone-forming strategies for the treatment of osteoporosis that resulted from these discoveries, such as antibodies against sclerostin, are discussed as well.

Carnosol suppresses RANKL‐induced osteoclastogenesis and attenuates titanium particles‐induced osteolysis

“…Bone, a dynamic tissue, experiences continuous remodeling of osteoblast formation and osteoclast resorption (Hadjidakis & Androulakis, 2006; B. Zhao, 2017). The imbalance of osteoclastic resorption and osteoblastic bone formation may result in pathological conditions of bone structure, including osteoporosis, osteonecrosis, and Paget's disease (Boudin & Van Hul, 2017). Osteolytic disease occurs when the enhancement of formation and function for osteoclasts, or the relatively impairment of formation and function for osteoblasts (Kular, Tickner, Chim, & Xu, 2012; Xu et al, 2009).…”

“…*p < .05 and **p < .01 for statistical significance comparing the treatment group with control groups The excessive osteoclast formation and activity are featured in a wide range of osteolytic diseases (T Nakamura et al, 2007),. including osteoporosis(Boudin & Van Hul, 2017), periodontitis (D. E Lee et al, 2015),. rheumatoid arthritis(Durand et al, 2011; Nose et al, 2009), and the aseptic loosening of orthopedic implants(Jamsen et al, 2017).…”

D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density

“…A recent systematic review and meta-analysis study demonstrated significant correlations between vitamin D receptor (VDR) polymorphisms, such as VDR ApaI and VDR FokI, and susceptibility to postmenopausal osteoporosis 42 . Such studies have offered us the opportunity to understand the bone density issue at the genetic level and increased our knowledge about osteoporosis 43 . A GWAS study integrating co-expression network data found that SPTBN1 (spectrin, beta, non-erythrocytic 1) and MARK3 (MAP/microtubule affinity-regulating kinase 3) were causal genes at BMD GWAS loci 44 .…”

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

“…At the beginning of this century, an additional role of WNT signaling was discovered following new gene identifications in some rare monogenic skeletal dysplasias. As explained in detail below, the study of conditions with either decreased or increased bone mass resulted in the identification of mutations in several genes involved in especially canonical WNT signaling (5). The most recent revision of the nosology and classification of genetic skeletal disorders (6) includes 461 different diseases.…”