Osteopontin Deficiency Induces Parathyroid Hormone Enhancement of Cortical Bone Formation

Intermittent PTH treatment increases cancellous bone mass in osteoporosis patients; however, it reveals diverse effects on cortical bone mass. Underlying molecular mechanisms for anabolic PTH actions are largely unknown. Because PTH regulates expression of osteopontin (OPN) in osteoblasts, OPN could be one of the targets of PTH in bone. Therefore, we examined the role of OPN in the PTH actions in bone. Intermittent PTH treatment neither altered whole long-bone bone mineral density nor changed cortical bone mass in wild-type 129 mice, although it enhanced cancellous bone volume as reported previously. In contrast, OPN deficiency induced PTH enhancement of whole-bone bone mineral density as well as cortical bone mass. Strikingly, although PTH suppressed periosteal bone formation rate (BFR) and mineral apposition rate (MAR) in cortical bone in wild type, OPN deficiency induced PTH activation of periosteal BFR and MAR. In cancellous bone, OPN deficiency further enhanced PTH increase in BFR and MAR. Analysis on the cellular bases for these phenomena indicated that OPN deficiency augmented PTH enhancement in the increase in mineralized nodule formation in vitro. OPN deficiency did not alter the levels of PTH enhancement of the excretion of deoxypyridinoline in urine, the osteoclast number in vivo, and tartrate-resistant acid phosphatase-positive cell development in vitro. These observations indicated that OPN deficiency specifically induces PTH activation of periosteal bone formation in the cortical bone envelope.

Download Full-text

Fat Mass Exerts a Greater Effect on Cortical Bone Mass in Girls than Boys

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1907 ◽

2010 ◽

Vol 95 (2) ◽

pp. 699-706 ◽

Cited By ~ 53

Author(s):

Adrian Sayers ◽

Jonathan H. Tobias

Keyword(s):

Bone Mineral Density ◽

Bone Mass ◽

Cortical Bone ◽

Bone Mineral ◽

Fat Mass ◽

Quantitative Computed Tomography ◽

Positive Association ◽

Mineral Density ◽

Cortical Bone Mineral Density ◽

Cortical Bone Mass

Abstract Context: It is unclear whether fat mass (FM) and lean mass (LM) differ in the way they influence cortical bone development in boys and girls. Objective: The aim of the study was to investigate the contributions of total body FM and LM to parameters related to cortical bone mass and geometry. Design/Setting: We conducted a longitudinal birth cohort study, the Avon Longitudinal Study of Parents and Children. Participants: A total of 4005 boys and girls (mean age, 15.5 yr) participated in the study. Outcome Measures: We measured cortical bone mass, cortical bone mineral content (BMCC), cortical bone mineral density, periosteal circumference (PC), and endosteal circumference by tibial peripheral quantitative computed tomography. Results: LM had a similar positive association with BMCC in boys and girls [regression coefficients with 95% confidence interval (CI); P for gender interactions: boys/girls, 0.952 (0.908, 0.997); P = 0.85]. However, the mechanisms by which LM influenced bone mass differed according to gender because LM was positively associated with PC more strongly in girls [boys, 0.579 (0.522, 0.635); girls, 0.799 (0.722, 0.875); P < 0.0001], but was only associated with cortical bone mineral density in boys [boys, 0.443 (0.382, 0.505); girls, 0.014 (−0.070, 0.097); P < 0.0001]. There was a stronger positive association between FM and BMCC in girls [boys, 0.227 (0.185, 0.269); girls, 0.355 (0.319, 0.392); P < 0.0001]. This reflected both a greater positive association of FM with PC in girls [boys, 0.213 (0.174, 0.253); girls, 0.312 (0.278, 0.347); P = 0.0002], and a stronger negative association with endosteal circumferencePC [boys, −0.059 (−0.096, 0.021); girls, −0.181 (−0.215, −0.146); P < 0.0001]. Conclusions: Whereas LM stimulates the accrual of cortical bone mass to a similar extent in boys and girls, FM is a stronger stimulus for accrual of cortical bone mass in girls, reflecting a greater tendency in females for FM to stimulate periosteal growth and suppress endosteal expansion.

Download Full-text

Osteoblast‐derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans

The FASEB Journal ◽

10.1096/fj.201900707r ◽

2019 ◽

Vol 33 (10) ◽

pp. 11163-11179 ◽

Cited By ~ 5

Author(s):

Sofia Movérare-Skrtic ◽

Karin H. Nilsson ◽

Petra Henning ◽

Thomas Funck-Brentano ◽

Maria Nethander ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mass ◽

Cortical Bone ◽

Bone Mineral ◽

Mineral Density ◽

Cortical Bone Mass

Download Full-text

IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation

Scientific Reports ◽

10.1038/s41598-021-89625-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wida Razawy ◽

Celso H. Alves ◽

Marijke Koedam ◽

Patrick S. Asmawidjaja ◽

Adriana M. C. Mus ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Bone Growth ◽

Osteoclast Differentiation ◽

Bone Homeostasis ◽

Littermate Control ◽

Cortical Bone Mass

AbstractThe IL-23 receptor (IL-23R) signaling pathway has pleiotropic effects on the differentiation of osteoclasts and osteoblasts, since it can inhibit or stimulate these processes via different pathways. However, the potential role of this pathway in the regulation of bone homeostasis remains elusive. Therefore, we studied the role of IL-23R signaling in physiological bone remodeling using IL-23R deficient mice. Using µCT, we demonstrate that 7-week-old IL-23R−/− mice have similar bone mass as age matched littermate control mice. In contrast, 12-week-old IL-23R−/− mice have significantly lower trabecular and cortical bone mass, shorter femurs and more fragile bones. At the age of 26 weeks, there were no differences in trabecular bone mass and femur length, but most of cortical bone mass parameters remain significantly lower in IL-23R−/− mice. In vitro osteoclast differentiation and resorption capacity of 7- and 12-week-old IL-23R−/− mice are similar to WT. However, serum levels of the bone formation marker, PINP, are significantly lower in 12-week-old IL-23R−/− mice, but similar to WT at 7 and 26 weeks. Interestingly, Il23r gene expression was not detected in in vitro cultured osteoblasts, suggesting an indirect effect of IL-23R. In conclusion, IL-23R deficiency results in temporal and long-term changes in bone growth via regulation of bone formation.

Download Full-text

Influence of Gastrectomy on Cortical and Cancellous Bones in Rats

Gastroenterology Research and Practice ◽

10.1155/2013/381616 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Jun Iwamoto ◽

Yoshihiro Sato ◽

Hideo Matsumoto

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Cancellous Bone ◽

Femoral Diaphysis ◽

Control Group ◽

Sham Operation ◽

Sprague Dawley ◽

Osteoid Surface ◽

Cortical Bone Mass

The aim of the present study was to examine the influence of gastrectomy (GX) on cortical and cancellous bones in rats. Twenty male Sprague-Dawley rats were randomized into the two groups of 10 animals each: a sham operation (control) group and a GX group. Seven weeks after surgery, the bone mineral content and density (BMC and BMD, resp.) and the mechanical strength of the femur were determined, and bone histomorphometric analyses were performed on the tibia. GX induced decreases in the BMC, BMD, ultimate force, work to failure, and stiffness of the femoral distal metaphysis and the BMC, BMD, and ultimate force of the femoral diaphysis. GX induced a decrease in cancellous bone mass, characterized by an increased osteoid thickness, osteoid surface, osteoid volume, and bone formation. GX also induced a decrease in cortical bone mass, characterized by increased endocortical bone resorption. The GX induced reductions in the bone mass and strength parameters were greater in cancellous bone than in cortical bone. The present study showed that the response of bone formation, resorption, and osteoid parameters to GX and the degree of GX-induced osteopenia and the deterioration of bone strength appeared to differ between cortical and cancellous bones in rats.

Download Full-text

Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2018.2335 ◽

2018 ◽

Vol 18 (2) ◽

pp. 206-210 ◽

Cited By ~ 3

Author(s):

Mehmet Dagli ◽

Ali Kutlucan ◽

Sedat Abusoglu ◽

Abdulkadir Basturk ◽

Mehmet Sozen ◽

...

Keyword(s):

Bone Mineral Density ◽

Vitamin D ◽

Bone Formation ◽

Bone Mass ◽

Bone Mineral ◽

Type I ◽

Healthy Controls ◽

Mineral Density ◽

Lymphocyte Ratio ◽

Significant Difference

A decrease in bone mass is observed in hemophilic patients. The aim of this study was to evaluate bone mineral density (BMD), parathyroid hormone (PTH), 25-hydroxy vitamin D (vitamin D), and a bone formation and resorption marker, procollagen type I N-terminal propeptide (PINP) and urinary N-terminal telopeptide (uNTX) respectively, in hemophilic patients and healthy controls. Laboratory parameters related to the pathogenesis of bone loss such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were also evaluated. Thirty-five men over 18 years of age, with severe hemophilia (A and B) and receiving secondary prophylaxis, were included in the study. The same number of age-, sex-, and ethnicity-matched healthy controls were evaluated. Anthropometric, biochemical, and hormonal parameters were determined in both groups. No significant difference in anthropometric parameters was found between the two groups. The BMD was low in 34% of hemophilic patients. Vitamin D, calcium, and free testosterone levels were significantly lower (p < 0.001, p = 0.011, p < 0.001, respectively), while PTH, PINP, and activated partial thromboplastin time (aPTT) levels were significantly higher (p < 0.014, p = 0.043, p < 0.001, respectively), in hemophilic patients compared to controls. There was no significant difference between the two groups in NLR, PLR, phosphorus, thyroid-stimulating hormone, and uNTX level. The reduction of bone mass in hemophilic patients may be evaluated using the markers of bone formation and resorption, enabling early detection and timely treatment.

Download Full-text

A New Synthetic Steroid, Osaterone Acetate (TZP-4238), Increases Cortical Bone Mass and Strength by Enhancing Bone Formation in Ovariectomized Rats

Journal of Bone and Mineral Research ◽

10.1359/jbmr.1997.12.4.590 ◽

1997 ◽

Vol 12 (4) ◽

pp. 590-597 ◽

Cited By ~ 13

Author(s):

Hiroaki Fuse ◽

Seiji Fukumoto ◽

Hideyuki Sone ◽

Yoshiko Miyata ◽

Tomoyuki Saito ◽

...

Keyword(s):

Bone Formation ◽

Bone Mass ◽

Cortical Bone ◽

Ovariectomized Rats ◽

Cortical Bone Mass

Download Full-text

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

Journal of Endocrinology ◽

10.1530/joe-18-0153 ◽

2018 ◽

Vol 238 (1) ◽

pp. 13-23 ◽

Cited By ~ 12

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.

Download Full-text

High bone mass gained by exercise in growing male mice is increased by subsequent reduced exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.01169.2003 ◽

2004 ◽

Vol 97 (3) ◽

pp. 806-810 ◽

Cited By ~ 27

Author(s):

Jian Wu ◽

Xin Xiang Wang ◽

Mitsuru Higuchi ◽

Kazuhiko Yamada ◽

Yoshiko Ishimi

Keyword(s):

Bone Mineral Density ◽

Bone Formation ◽

Bone Mass ◽

Exercise Group ◽

Mineral Apposition Rate ◽

Male Mice ◽

Sedentary Control ◽

Mineral Density ◽

High Bone Mass ◽

High Bone

Exercise-induced bone gains are lost if exercise ceases. Therefore, continued exercise at a reduced frequency or intensity may be required to maintain these benefits. In this study, we evaluated whether 4 wk of reduced exercise after 4 wk of running exercise in growing male mice results in the maintenance of high bone mass. Five-week-old mice were divided into the following groups: 1) baseline control; 2) 4-wk control; 3) 4-wk exercise; 4) 8-wk control; 5) 4-wk exercise followed by 4-wk cessation of training; and 6) 4-wk exercise followed by reduced exercise at half the frequency. The regimen consisted of exercise 6 days/wk, and the reduced exercise regimen consisted of running 3 days/wk on a treadmill for 30 min/day, at 12 m/min on a 10° uphill slope. Running exercise significantly increased bone mineral density of the femur, periosteal mineral apposition rate, bone formation rate, percent labeled perimeter at the midfemur, and osteogenic activity of bone marrow cells. However, these parameters declined to the age-matched sedentary control after cessation of training. In contrast, the reduced exercise group had significantly higher mineral apposition rate compared with those of the sedentary control and cessation of training groups. Furthermore, bone mineral density for the reduced exercise group was significantly higher than those for the other groups. These results suggest that the high bone formation gained through exercise can be maintained, and bone mass was further increased by subsequent exercise even if the exercise frequency is reduced.

Download Full-text

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520408112 ◽

2015 ◽

Vol 112 (48) ◽

pp. 14972-14977 ◽

Cited By ~ 24

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.

Download Full-text