Abstract
Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage–specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.—Movérare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans.
Highlights
ABBREVIATIONS: a-MEM, a-minimum essential medium; mCT, micro–computed tomography; ALP, alkaline phosphatase; BMD, bone mineral density; bone marrow–derived macrophages (BMMs), bone marrow–derived macrophage; BV/TV, bone volume/tissue volume; Computed tomography (CT), computed tomography; CTX, C-terminal type I collagen; Dual-energy X-ray absorptiometry (DXA), dual-energy X-ray absorptiometry; Estimated BMD (eBMD), estimated bone mineral density; M-CSF, macrophage colony-stimulating factor; PGK-1, phosphoglycerate kinase 1; RANKL, receptor activator of nuclear factor k-B ligand; siRNA, small interfering RNA; TRAP, tartrate-resistant acid phosphatase; single nucleotide polymorphisms (SNPs), single nucleotide polymorphism; Wls, Wntless; wingless-type MMTV integration site family members (WNTs), Wingless-type MMTV integration site family member; WT, wild type
Because Notum expression was high in cortical bone, we hypothesized that the cortical bone phenotype in the heterozygote female Notum-inactivated mice might be caused by lack of Notum expression by osteoblast lineage cells in cortical bone
We demonstrate that osteoblast lineage–derived NOTUM is a crucial determinant of cortical bone mass and strength via regulation of periosteal bone formation in mice and that genetic variants in the NOTUM locus are robustly associated with BMD in humans
Summary
ABBREVIATIONS: a-MEM, a-minimum essential medium; mCT, micro–computed tomography; ALP, alkaline phosphatase; BMD, bone mineral density; BMM, bone marrow–derived macrophage; BV/TV, bone volume/tissue volume; CT, computed tomography; CTX, C-terminal type I collagen; DXA, dual-energy X-ray absorptiometry; eBMD, estimated bone mineral density; M-CSF, macrophage colony-stimulating factor; PGK-1, phosphoglycerate kinase 1; RANKL, receptor activator of nuclear factor k-B ligand; siRNA, small interfering RNA; TRAP, tartrate-resistant acid phosphatase; SNP, single nucleotide polymorphism; Wls, Wntless; WNT, Wingless-type MMTV integration site family member; WT, wild type. Lifelong NOTUM inactivation in mice, using the less precise gene trapping technique, resulted in developmental defects involving the kidneys (unilateral agenesis) and teeth (dental dysplasia) as well as reduced embryonic viability [12] Referring to this mouse model of NOTUM inactivation, developed in a large-scale screen of multiple mouse models, it was recently reported that the mice surviving to adulthood had increased cortical bone mass, but the underlying mechanisms for the skeletal phenotype in these mice were not evaluated [13]. We aimed to determine if genetic variation in the NOTUM locus is associated with bone mass in humans
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