Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice

Ohlsson, Claes; Henning, Petra; Nilsson, Karin; Wu, Jianyao; Gustafsson, Kristian; Sjögren, Klara; Törnqvist, Anna E.; Koskela, Antti; Zhang, Fuping; Lagerquist, Marie K; Poutanen, Matti; Tuukkanen, Juha; Lerner, Ulf H.; Movérare‐Skrtic, Sofia

doi:10.1530/joe-18-0020

Cited by 33 publications

(41 citation statements)

References 33 publications

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“…WNT16 also has life-long skeletal actions, as conditional overexpression of human WNT16 in adult transgenic mice increases cortical bone thickness. 44…”

Section: Discussionmentioning

confidence: 99%

NOTUM inhibition increases endocortical bone formation and bone strength

et al. 2019

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The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum−/− mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

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“…WNT16 also has life-long skeletal actions, as conditional overexpression of human WNT16 in adult transgenic mice increases cortical bone thickness. 44…”

Section: Discussionmentioning

confidence: 99%

NOTUM inhibition increases endocortical bone formation and bone strength

et al. 2019

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“…We have shown in zebrafish that wnt16 controls chondrocyte proliferation and migration in the joint region. Wnt16 is also linked to hip geometry [ 83 ], altered cortical bone thickness [ 84 , 85 ], the response of chondrocytes to injury and to OA [ 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

The mechanical impact ofcol11a2loss on joints;col11a2mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis

Lawrence

Kague

Aggleton

et al. 2018

Phil. Trans. R. Soc. B

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Collagen is the major structural component of cartilage, and mutations in the genes encoding type XI collagen are associated with severe skeletal dysplasias (fibrochondrogenesis and Stickler syndrome) and early-onset osteoarthritis (OA). The impact of the lack of type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants, type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using atomic force microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint is broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using finite element analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early-onset OA. Taken together, our data demonstrate a key role for type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

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“…Although the specifics behind its mechanisms are unclear, GWASs show that polymorphisms of the WNT16 locus associate with cortical bone thickness, BMD, and osteoporotic fracture risk in large observational studies and variations in WNT16 may also impact individual peak bone mass (18, 52, 53). These findings are echoed in in vivo studies as Wnt16 KO mice have reduced cortical thickness and bone strength leading to spontaneous peripheral fractures (54).…”

Section: Paths To Monogenic Osteoporosismentioning

confidence: 96%

New Insights Into Monogenic Causes of Osteoporosis

et al. 2019

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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.

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Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice

Cited by 33 publications

References 33 publications

NOTUM inhibition increases endocortical bone formation and bone strength

NOTUM inhibition increases endocortical bone formation and bone strength

The mechanical impact ofcol11a2loss on joints;col11a2mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis

New Insights Into Monogenic Causes of Osteoporosis

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