We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated β-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.

In former views hormones, calcium, vitamin D and other humoral and nonmechanical agents dominated control of postnatal bone strength (and "mass") in children and adolescents. However later evidence that led to the Utah paradigm of skeletal physiology revealed that this control depends strongly on the largest mechanical loads on bones. Trauma excepted, muscles cause the largest loads and the largest bone strains, and these strains help to control the biological mechanisms that determine whole-bone strength. That makes the strength of children's load-bearing bones depend strongly on growing muscle strength and how bones respond to it. Most hormones and other nonmechanical agents that affect bone strength can help or hinder that "bone strength-muscle strength" relationship but cannot replace it. In addition some agents long thought to exert bone effects by acting directly on bone cells, affect muscle strength too. In that way they could affect bone strength indirectly. Such agents include growth hormone, adrenalcorticosteroid analogs, androgens, calcium, genes, vitamin D and its metabolites, etc. Thus bone and muscle do form a kind of operational unit. It is part of the Utah paradigm that supplements earlier views with later evidence and concepts. The paradigm explains how the "bone strength-muscle strength" relationship works. This article provides an overview of that physiology, and some of its implications for pediatric endocrinologists.