Acknooledgments 65 and BMP2 and OA have been found, suggesting that vari-
ability in gene expression is a susceptibility factor for the disease. The strongest evidence for a role in OA suscepti- bility comes from a SNP in the 5’ untranslated region (5’‐UTR) of BMP14/GDF5, rs143383, associated with OA [39]. rs143383 is a C/T transition and the OA‐associated T allele of rs143383 has been shown to produce less mRNA transcript compared with the ancestral C allele, indicating that reduced BMP14/GDF5 expression is likely to be the mechanism through which this OA susceptibility locus is working.
Brachydactyly (BD)
BD is a shortening of the hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Depending on the affected phalanges, five different types of brachydactyl- ies are categorized (BDA to BDE) including seven subgroups (BDA1 to BDA7).
Mutations in BMP14/GDF5 have been linked to isolated traits of different types of brachydactyly including BDA1, BDA2, and BDC [40]. Dominant‐
negative mutations in BMPR1B and a specific missense mutation in BMP14/GDF5 are known to cause isolated brachydactyly type BDA2 due to a loss of interaction between BMPR1B and BMP‐14/GDF‐5 [41]. A mutation in BMPR1B (R486Q) is associated with either BDA2 or a BDC/symphalangism (SYM1)‐like phenotype [42].
Duplication of a regulatory element that affects the expression of BMP2 is associated with BDA2 [43].
Symphalangism (SYM)
SYM is an uncommon condition characterized by fusion of the joints of the fingers or toes. Activating mutations in BMP14/GDF5 result in increased chondrogenic activity as described for proximal SYM and the multiple synostoses syndrome 2 [44]. A mutation in BMP14 (R438L) leads to a loss of receptor‐binding specificity, causing the SYM phenotype [41].
BMPS AND BONE MAINTENANCE
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Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. Edited by John P. Bilezikian.
© 2019 American Society for Bone and Mineral Research. Published 2019 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/asbmrprimer
9
INTRODUCTION
Wnt/β‐catenin signaling plays a number of key roles in regulating embryogenesis, organogenesis, cell fate deter- mination, and differentiation. Our knowledge of Wnt signaling is still expanding, with recent work identifying several mechanisms by which the pathway is fine‐tuned at several levels, including the activity of Wnt as a ligand and the regulation of Wnt receptor protein levels. We are becoming more and more aware of the complexity of Wnt regulation of bone homeostasis, and we are trying to manipulate this pathway to cure human skeletal diseases.