cortical bone mass
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2021 ◽  
Author(s):  
Jean Jiang

Mechanical stimulation, such as physical exercise, is essential for bone formation and health. Here, we demonstrate the critical role of osteocytic Cx43 hemichannels in anabolic function of bone in response to mechanical loading. Two transgenic mouse models, R76W and Δ130-136, expressing dominant-negative Cx43 mutants in osteocytes were adopted. Mechanical loading of tibial bone increased cortical bone mass and mechanical properties in wild-type and gap junction-impaired R76W mice through increased PGE2, endosteal osteoblast activity, and decreased sclerostin. These anabolic responses were impeded in gap junction/hemichannel-impaired Δ130-136 mice and accompanied by increased endosteal osteoclast activity. Specific inhibition of Cx43 hemichannels by Cx43(M1) antibody suppressed PGE2 secretion and impeded loading-induced endosteal osteoblast activity, bone formation and anabolic gene expression. PGE2 administration rescued the osteogenic response to mechanical loading impeded by impaired hemichannels. Together, osteocytic Cx43 hemichannels could be a potential new therapeutic target for treating bone loss and osteoporosis.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wida Razawy ◽  
Celso H. Alves ◽  
Marijke Koedam ◽  
Patrick S. Asmawidjaja ◽  
Adriana M. C. Mus ◽  
...  

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.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A231-A232
Author(s):  
Michela Palmieri ◽  
Teenamol E Joseph ◽  
Aaron Warren ◽  
Horacio Gomez-acevedo ◽  
Jinhu Xiong ◽  
...  

Abstract Oxidized phospholipids (OxPL), such as oxidized phosphatidylcholine, are generated by oxidative stress (OS)-induced lipid peroxidation. E06 IgM is a natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, but not native PLs. Generation of transgenic mice expressing a single chain (scFv) form of its antigen-binding domain, “E06-scFv” mice, protects against atherosclerosis, hepatic steatosis and high fat diet-induced loss of bone mass. In addition, E06-scFv increases cancellous and cortical bone mass in both male and female adult mice fed chow diet, by increasing bone formation. Age-related bone loss is associated with increased OS and lipid peroxidation, and is characterized by a reduction in osteoblast number and bone formation. Oxidative stress is involved also in the bone loss caused by sex-steroid deficiency and elevated OS markers are found in unloading-induced bone loss, raising the possibility that an increase of OxPLs induced by OS might be contributing to the pathogenesis of these conditions as well. We aged homozygous E06-scFv transgenic female and male mice and their wild-type littermates up to 22 and 24 months respectively. Serial DXA BMD every 3 months showed that overexpression of E06-scFv attenuated the age-associated bone loss in both sexes. In addition, male and female E06-scFv transgenic mice also accumulated less fat mass than WT littermates during aging. Micro-CT analysis revealed that E06-scFv attenuated the age-associated decline in cancellous, but not cortical, bone mass. The histological analysis of the vertebrae indicated that the aged E06-scFv transgenic mice had increased osteoblasts and decreased osteoclasts compared to the WT mice. To investigate whether the beneficial effect of the E06-scFv could be seen after ovariectomy, 4.5 month old E06-scFv homozygous females and WT controls were ovariectomized (OVX). DXA and micro-CT measurements 6 weeks post- surgery indicated that, unlike aging, E06-scFv did not protect against OVX-induced bone loss in either the cancellous or the cortical compartment. Lastly, we tail-suspended 5.5 month old male mice and sacrificed them 21 days later. E06-scFv transgenic mice had similar cortical bone loss compared to WT mice. In conclusion, the E06-scFV transgene attenuates the age-associated cancellous bone loss in both female and male mice, but has no effect on the OVX- or unloading-induced bone loss. These results fully support our hypothesis that an increase in PC-OxPLs with age, caused at least in part by a decrease in natural anti-PC antibodies, contributes to the age-associated bone loss. This evidence provides proof of concept that blocking PC-OxPLs represents a therapeutic approach to countering the increase of PC-OxPLs with age and their adverse effects on age-related bone loss as well as atherosclerosis and NASH. It also confirms that the mechanisms of cancellous and cortical bone loss are distinct.


Bone Reports ◽  
2021 ◽  
Vol 14 ◽  
pp. 100885
Author(s):  
Behzad Javaheri ◽  
Amy Lock ◽  
Mark Hopkinson ◽  
Samuel Monzem ◽  
Yu-Mei Chang ◽  
...  

Author(s):  
Karin H. Nilsson ◽  
Petra Henning ◽  
Maha El Shahawy ◽  
Jianyao Wu ◽  
Antti Koskela ◽  
...  

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.


Author(s):  
Maria G Vogiatzi ◽  
Shanlee M Davis ◽  
Judith L Ross

Abstract Introduction Klinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood. Objective To determine the effects of androgen treatment on bone mass in children with KS. Study design Randomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n= 38) versus placebo (PL; n= 40) for 2 years in boys with KS (ages 4- 12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation scores (BHI SDS). Results BHI SDS was similar between groups at baseline (-0.46±1.1 vs. -0.34±1.0 OX vs. PL, p>0.05) and higher in the OX group at 2 years (-0.1 + 1.3 vs. -0.53 + 0.9, OX vs. PL, p< 0.01). At baseline, BHI SDS values of all subjects were not normally distributed with 25.7% of subjects plotted below -1 SDS (p<0.001), suggesting a deficit in bone mass. 13.5% of subjects had sustained a fracture and their BHI SDS was lower than those with no fractures (-1.6 + 1.3 vs. -0.3 + 1.0, p= 0.004). Conclusions Bone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.


2020 ◽  
Vol 21 (22) ◽  
pp. 8638
Author(s):  
Noriko Funato ◽  
Yuki Taga ◽  
Lindsay E. Laurie ◽  
Chisa Tometsuka ◽  
Masashi Kusubata ◽  
...  

Temporal and/or spatial alteration of collagen family gene expression results in bone defects. However, how collagen expression controls bone size remains largely unknown. The basic helix-loop-helix transcription factor HAND1 is expressed in developing long bones and is involved in their morphogenesis. To understand the functional role of HAND1 and collagen in the postnatal development of long bones, we overexpressed Hand1 in the osteochondroprogenitors of model mice and found that the bone volumes of cortical bones decreased in Hand1Tg/+;Twist2-Cre mice. Continuous Hand1 expression downregulated the gene expression of type I, V, and XI collagen in the diaphyses of long bones and was associated with decreased expression of Runx2 and Sp7/Osterix, encoding transcription factors involved in the transactivation of fibril-forming collagen genes. Members of the microRNA-196 family, which target the 3′ untranslated regions of COL1A1 and COL1A2, were significantly upregulated in Hand1Tg/+;Twist2-Cre mice. Mass spectrometry revealed that the expression ratios of alpha 1(XI), alpha 2(XI), and alpha 2(V) in the diaphysis increased during postnatal development in wild-type mice, which was delayed in Hand1Tg/+;Twist2-Cre mice. Our results demonstrate that HAND1 regulates bone size and morphology through osteochondroprogenitors, at least partially by suppressing postnatal expression of collagen fibrils in the cortical bones.


2020 ◽  
pp. 153537022096273
Author(s):  
Ge Yang ◽  
Hui Yu ◽  
Yaoxi Liu ◽  
Weihua Ye ◽  
Guanghui Zhu ◽  
...  

Treatment of congenital pseudarthrosis of the tibia (CPT) still is full of challenges in pediatric orthopedist. Serum-derived exosomes (SDEs) have been proven to be participated in bone remodeling. However, the molecular changes in SDEs of CPT children and their pathologies have not been elucidated. In this study, SDEs were isolated and purified from CPT patients (CPT-SDEs) associated with neurofibromatosis type 1 (NF1) and normal children (Norm-SDEs). Then we obtained the proteomics profile of SDEs by combining liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tandem mass tag label-based quantitation. In vitro, the efficacy of SDEs on osteoblastic differentiation of MC3T3-E1 cells and osteoclastogenesis ability of RAW264.7 cells were evaluated by quantitative real-time PCR (qRT-PCR) and cytochemical staining. In vivo, we used micro-CT to assess cortical bone mass and trabecular microstructures to reflect the influence of SDEs on bone remodeling after injection into the tail vein of rats. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. These proteins have multiple biological functions associated with cellular metabolic processes, catalytic activity, and protein binding, which are important for cell differentiation and proliferation. In vitro, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis of RAW264.7 cells. Injection of CPT-SDEs into the tail vein for two months resulted in bone loss in rats, as indicated by the decrease in trabecular and cortical bone mass. Our findings demonstrated the differences in proteins in SDEs between normal and CPT children with NF1. These differentially expressed proteins in CPT-SDEs contributed to deteriorating trabecular bone microstructures by inhibiting bone formation and stimulating bone resorption. Impact statement Congenital pseudarthrosis of the tibia (CPT) is an uncommon and puzzling disease associated with a high rate of disability. To date, the biological mechanisms related to this disease have largely not been elucidated. In this study, we determined the biological functions of serum-derived exosomes (SDEs) from children with neurofibromatosis type 1 (NF1) associated with CPT (CPT-SDEs) and compared their proteomic profiles with those of SDEs from normal children. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. In addition, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis ability of RAW264.7 cells. Moreover, injecting CPT-SDEs into the tail veins led to bone loss in rats, as detected by the reduction in trabecular and cortical bone mass. These findings indicate that CPT-SDEs impair bone quality, which may provide a reasonable explanation for the low bone quality and tibial nonunion in children with NF1 associated with congenital tibial pseudarthrosis.


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