scholarly journals Mmp-13 deletion in cells of the mesenchymal lineage increases bone mass, decreases endocortical osteoclast number, and attenuates the cortical bone loss caused by estrogen deficiency in mice

2021 ◽  
Author(s):  
Filipa Ponte ◽  
Ha-Neui Kim ◽  
Aaron Warren ◽  
Srividhya Iyer ◽  
Li Han ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Protective Effect ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Cortical Thickness ◽  
Mesenchymal Cell ◽  
Estrogen Deficiency ◽  
Cortical Bone Loss ◽  
Osteoclast Number

The protective effect of estrogens against cortical bone loss is mediated via direct actions on mesenchymal lineage cells, but functional evidence for the precise molecular mechanism(s) and the mediators of these effects has only recently began to emerge. We report that the matrix metalloproteinase 13 (MMP-13) is the highest up-regulated gene in calvaria or bone marrow cells from mice lacking the estrogen receptor (ER) alpha in osteoprogenitors. We, therefore, generated mice with conditional Mmp-13 deletion in Prrx1 expressing cells ( Mmp-13 ?Prrx1 ) and compared the effect of estrogen deficiency on their bone phenotype to that of control littermates ( Mmp-13 f/f ). Femur and tibia length was decreased in sham-operated Mmp-13 ?Prrx1 mice as compared to Mmp1 3 f/f . Cortical thickness and trabecular bone volume in the femur and tibia were increased and osteoclast number at the endocortical surfaces was decreased in the sham-operated female Mmp13 ?Prrx1 mice; whereas bone formation rate was unaffected. Ovariectomy (OVX) caused a decrease of cortical thickness in the femur and tibia of Mmp-13 f/f control mice. This effect was attenuated in the Mmp-13 ? Prrx1 mice; but the decrease of trabecular bone caused by OVX was not affected. These results reveal that mesenchymal cell–derived MMP-13 regulates osteoclast number, bone resorption, and bone mass. We have recently reported that the loss of cortical, but not trabecular bone, caused by OVX is also attenuated in Cxcl12 ?Prrx1 mice. Together with the present report, this functional genetic evidence provides proof of principle that increased production of mesenchymal cell-derived factors, such as CXCL12 and MMP-13, are important mediators of the adverse effect of estrogen deficiency on cortical, but not trabecular, bone. Therefore, the mechanisms responsible for the protective effect of estrogens on these two major bone compartments are different.

scholarly journals Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice

2016 ◽  
Vol 311 (3) ◽  
pp. E587-E593 ◽  
Author(s):  
Marilina Piemontese ◽  
Jinhu Xiong ◽  
Yuko Fujiwara ◽  
Jeff D. Thostenson ◽  
Charles A. O'Brien
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Cortical Bone ◽  
Cortical Thickness ◽  
Calcium Deficiency ◽  
Osteoclast Formation ◽  
Mrna Abundance ◽  
Cortical Porosity ◽  
Cortical Bone Loss ◽  
Osteoclast Number

Glucocorticoid excess is a major cause of low bone mass and fractures. Glucocorticoid administration decreases cortical thickness and increases cortical porosity in mice, and these changes are associated with increased osteoclast number at the endocortical surface. Receptor activator of NF-κB ligand (RANKL) produced by osteocytes is required for osteoclast formation in cancellous bone as well as the increase in cortical bone resorption caused by mechanical unloading or dietary calcium deficiency. However, whether osteocyte-derived RANKL also participates in the increase in bone resorption caused by glucocorticoid excess is unknown. To address this question, we examined the effects of prednisolone on cortical bone of mice lacking RANKL production in osteocytes. Prednisolone administration increased osteoclast number at the endocortical surface, increased cortical porosity, and reduced cortical thickness in control mice, but none of these effects occurred in mice lacking RANKL in osteocytes. Prednisolone administration did not alter RANKL mRNA abundance but did reduce osteoprotegerin (OPG) mRNA abundance in osteocyte-enriched cortical bone. Similarly, dexamethasone suppressed OPG but did not increase RANKL production in cortical bone organ cultures and primary osteoblasts. These results demonstrate that RANKL produced by osteocytes is required for the cortical bone loss caused by glucocorticoid excess but suggest that the changes in endocortical resorption are driven by reduced OPG rather than elevated RANKL expression.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

Low dose of human PTH(1-34) improved tibial subcortical bone mass without further cortical bone loss in adult intact beagles

1998 ◽  
Vol 16 (2) ◽  
pp. 96-99 ◽  
Author(s):  
Liu Zhang ◽  
Hideaki E. Takahashi ◽  
Tatsuhiko Tanizawa ◽  
Naoto Endo ◽  
Noriaki Yamamoto ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Cortical Bone ◽  
Low Dose ◽  
Cortical Bone Loss

scholarly journals The bone-sparing effects of estrogen and WNT16 are independent of each other

2015 ◽  
Vol 112 (48) ◽  
pp. 14972-14977 ◽  
Author(s):  
Sofia Movérare-Skrtic ◽  
Jianyao Wu ◽  
Petra Henning ◽  
Karin L. Gustafsson ◽  
Klara Sjögren ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Integration Site ◽  
Mineral Density ◽  
Trabecular Bone Mass ◽  
Sparing Effect ◽  
Total Body ◽  
Cortical Bone Mass

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.

Relation of axial bone mass to habitual calcium intake and to cortical bone loss in healthy early postmenopausal women

Maturitas ◽  
1991 ◽  
Vol 13 (1) ◽  
pp. 85
Author(s):  
E.C.H. Van Beresteijn ◽  
M.A. Van't Hof ◽  
H. De Waard ◽  
J.A. Raymakers ◽  
S.A. Duursma
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Cortical Bone ◽  
Postmenopausal Women ◽  
Calcium Intake ◽  
Cortical Bone Loss ◽  
Early Postmenopausal Women

Relation of axial bone mass to habitual calcium intake and to cortical bone loss in healthy early postmenopausal women

Bone ◽  
1990 ◽  
Vol 11 (1) ◽  
pp. 7-13 ◽  
Author(s):  
E.C.H. van Beresteijn ◽  
M.A. van't Hof ◽  
H. de Waard ◽  
J.A. Raymakers ◽  
S.A. Duursma
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Cortical Bone ◽  
Postmenopausal Women ◽  
Calcium Intake ◽  
Cortical Bone Loss ◽  
Early Postmenopausal Women

scholarly journals Sciatic neurectomy-related cortical bone loss exhibits delayed onset yet stabilises more rapidly than trabecular bone

Bone Reports ◽  
2021 ◽  
pp. 101116
Author(s):  
Samuel Monzem ◽  
Behzad Javaheri ◽  
Roberto Lopes de Souza ◽  
Andrew Anthony Pitsillides
Keyword(s):  
Bone Loss ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Cortical Bone Loss ◽  
Delayed Onset ◽  
Sciatic Neurectomy

Pamidronate prevents trabecular bone loss but fails to improve cortical bone loss induced by tail suspension in rats

Bone ◽  
1995 ◽  
Vol 17 (6) ◽  
pp. 603
Author(s):  
Y. Kodama ◽  
K. Nakayama ◽  
S. Fukumoto ◽  
H. Fuse ◽  
H. Takahashi ◽  
...  
Keyword(s):  
Bone Loss ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Tail Suspension ◽  
Cortical Bone Loss ◽  
Trabecular Bone Loss

scholarly journals Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen deficiency-induced bone loss

iScience ◽  
2021 ◽  
pp. 102224
Author(s):  
Juliane Lehmann ◽  
Sylvia Thiele ◽  
Ulrike Baschant ◽  
Tilman D. Rachner ◽  
Christof Niehrs ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Loss ◽  
Bone Mass ◽  
Estrogen Deficiency ◽  
High Bone Mass ◽  
High Bone

scholarly journals Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

2011 ◽  
Vol 212 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Rana Samadfam ◽  
Malaika Awori ◽  
Agnes Bénardeau ◽  
Frieder Bauss ◽  
Elena Sebokova ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Mineral ◽  
Combination Treatment ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Concomitant Treatment ◽  
Mineral Density ◽  
Ovx Rats

Peroxisome proliferator-activated receptor (PPAR) γ agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARα agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)+Feno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with Pio+Feno resulted in ∼50% lower fat mass gain compared with Pio treatment alone. Combination treatment with Pio+Feno partially prevented Pio-induced loss of bone mineral content (∼45%) and bone mineral density (BMD; ∼60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with Pio+Feno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the Pio+Feno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the Pio+Feno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARγ and PPARα may reduce the negative effects of PPARγ agonism on bone mass.

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