Vertebral cortical bone mass measurement by a new quantitative computer tomography method: Correlations with vertebral trabecular bone measurements

Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16−/− mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16-dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast-specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl-Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16−/− mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16−/− and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss.

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Caloric Restriction Decreases Cortical Bone Mass but Spares Trabecular Bone in the Mouse Skeleton: Implications for the Regulation of Bone Mass by Body Weight

Journal of Bone and Mineral Research ◽

10.1359/jbmr.080213 ◽

2008 ◽

Vol 23 (6) ◽

pp. 870-878 ◽

Cited By ~ 89

Author(s):

Mark W Hamrick ◽

Ke-Hong Ding ◽

Sumant Ponnala ◽

Serge L Ferrari ◽

Carlos M Isales

Keyword(s):

Body Weight ◽

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Caloric Restriction ◽

Cortical Bone Mass

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Osteocyte- and late Osteoblast-derived NOTUM Reduces Cortical Bone Mass in Mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00565.2020 ◽

2021 ◽

Author(s):

Karin H. Nilsson ◽

Petra Henning ◽

Maha El Shahawy ◽

Jianyao Wu ◽

Antti Koskela ◽

...

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Vertebral Fractures ◽

Volume Fraction ◽

Substantial Reduction ◽

Lumbar Vertebrae ◽

Bone Homeostasis ◽

Increased Risk ◽

Cortical Bone Mass

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on non-vertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1 expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur, but no change in trabecular bone volume fraction (BV/TV) in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared to control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce non-vertebral fracture risk.

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