New Insights Into Monogenic Causes of Osteoporosis

Abstract

Osteoporosis, characterized by deteriorated bone microarchitecture and low bone mineral density, is a chronic skeletal disease with high worldwide prevalence. Osteoporosis related to aging is the most common form and causes significant morbidity and mortality. Rare, monogenic forms of osteoporosis have their onset usually in childhood or young adulthood and have specific phenotypic features and clinical course depending on the underlying cause. The most common form is osteogenesis imperfecta linked to mutations in COL1A1 and COL1A2, the two genes encoding type I collagen. However, in the past years, remarkable advancements in bone research have expanded our understanding of the intricacies behind bone metabolism and identified novel molecular mechanisms contributing to skeletal health and disease. Especially high-throughput sequencing techniques have made family-based studies an efficient way to identify single genes causative of rare monogenic forms of osteoporosis and these have yielded several novel genes that encode proteins partaking in type I collagen modification or regulating bone cell function directly. New forms of monogenic osteoporosis, such as autosomal dominant osteoporosis caused by WNT1 mutations or X-linked osteoporosis due to PLS3 mutations, have revealed previously unidentified bone-regulating proteins and clarified specific roles of bone cells, expanded our understanding of possible inheritance mechanisms and paces of disease progression, and highlighted the potential of monogenic bone diseases to extend beyond the skeletal tissue. The novel gene discoveries have introduced new challenges to the classification and diagnosis of monogenic osteoporosis, but also provided promising new molecular targets for development of pharmacotherapies. In this article we give an overview of the recent discoveries in the area of monogenic forms of osteoporosis, describing the key cellular mechanisms leading to skeletal fragility, the major recent research findings and the essential challenges and avenues in future diagnostics and treatments.

Keywords: PLS3; Wnt signaling; bone metabolism; early-onset osteoporosis; osteogenesis imperfecta.

Figure 1

Manhattan plot displaying all lead SNPs independently associated with bone-related traits reported to the GWAS catalog as of September 2018. The associated SNPs highlight genomic regions important to bone. However, they each have only a minor effect on an individual's skeletal qualities and risk of osteoporosis and hence have limited use in clinical practice.

Figure 2

Schematic overview of bone cells and extracellular matrix components involved in regulating bone homeostasis. Receptor activator of nuclear factor kappa-B ligand (RANKL) binds to its conjugate receptor RANK on osteoclast cell surface to stimulate osteoclast differentiation and activity. Osteoprotegerin (OPG) inhibits RANK/RANKL-binding to inhibit bone resorption. WNT signaling pathway stimulates osteoblast function and bone formation. Sclerostin (SOST) and dickkopfs (DKK1), produced by the osteocytes, are two WNT antagonists that promote osteoclasts differentiation. Osteonectin, produced by the osteoblasts, binds calcium, hydroxyapatite and collagen type I and thus regulates bone mineralization. Plastin-3 (PLS3), expressed by the osteocytes, may also be involved in the mineralization of the extracellular matrix but its role in osteoprogenitors and other bone cells is yet to be confirmed.

Figure 3

Spinal magnetic resonance images of four WNT1 p.C218G mutation-positive subjects. (A) Thoracic spine of a 17-years-old female showing multiple Schmorl nodes (arrow). (B) Thoracic spine of a 44-years-old female showing exaggerated thoracic kyphosis. (C) Thoracic spine of a 76-years-old male showing several compressed vertebrae, kyphotic stature, and Schmorl hernia (arrow). (D) Lumbar spine of a 74-years-old female showing several compressed vertebrae and enlarged intervertebral discs (arrows). Reprinted from Mäkitie et al. (63) with permission from Elsevier.