Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.     

Submicron‐surface structured tricalcium phosphate ceramic enhances the bone regeneration in canine spine environment

Calcium phosphate ceramics with submicron‐scaled surface structure can trigger bone formation in non‐osseous sites and are expected to enhance bone formation in spine environment. In this study, two tricalcium phosphate ceramics having either a submicron‐scaled surface structure (TCP‐S) or a micron‐scaled one (TCP‐B) were prepared and characterized regarding their physicochemical properties. Granules (size 1–2 mm) of both materials were implanted on either left or right side of spinous process, between the two lumbar vertebrae (L3‐L4), and in paraspinal muscle of eight beagles. After 12 weeks of implantation, ectopic bone was observed in muscle in TCP‐S explants (7.7 ± 3.7%), confirming their ability to inductively form bone in non‐osseous sites. In contrast, TCP‐B implants did not lead to bone formation in muscle. Abundant bone (34.1 ± 6.6%) was formed within TCP‐S implants beside the two spinous processes, while limited bone (5.1 ± 4.5%) was seen in TCP‐B. Furthermore, the material resorption of TCP‐S was more pronounced than that of TCP‐B in both the muscle and spine environments. The results herein indicate that the submicron‐scaled surface structured tricalcium phosphate ceramic could enhance bone regeneration as compared to the micron‐scaled one in spine environment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1865–1873, 2016.     

Exogenous PTH and Endogenous 1,25‐Dihydroxyvitamin D Are Complementary in Inducing an Anabolic Effect on Bone

PTH and 1,25(OH)₂D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH)₂D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1‐34) to produce bone accrual in mice homozygous for the 1α(OH)ase‐null allele [1α(OH)ase^?/? mice] and in wildtype mice. In initial studies, 3‐mo‐old wildtype mice were either injected once daily (40 μg/kg) or infused continuously (120 μg/kg/d) with PTH(1–34) for up to 1 mo. Infused PTH reduced BMD, increased the bone resorption marker TRACP‐5b, and raised serum calcium but did not increase serum 1,25(OH)₂D. Injected PTH increased serum 1,25(OH)₂D and BMD, raised the bone formation marker osteocalcin more than did infused PTH, and did not produce sustained hypercalcemia as did PTH infusion. In subsequent studies, 3‐mo‐old 1α(OH)ase^?/? mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1–34) (40 μg/kg) either once daily or three times daily for 1 mo. In 1α(OH)ase^?/? mice, baseline bone volume (BV/TV) and bone formation (BFR/BS) were lower than in wildtype mice. PTH administered intermittently increased BV/TV and BFR/BS in a dose‐dependent manner, but the increases were always less than in wildtype mice. These studies show that exogenous PTH administered continuously resorbs bone without raising endogenous 1,25(OH)₂D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH)₂D, but 1,25(OH)₂D complements this PTH action. An increase in endogenous 1,25(OH)₂D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism.     

IL21R and PTH may underlie variation of femoral neck bone mineral density as revealed by a genome‐wide association study

Bone mineral density (BMD) measured at the femoral neck (FN) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. The specific genes influencing FN BMD remain largely unknown. To identify such genes, we first performed a genome‐wide association (GWA) analysis for FN BMD in a discovery sample consisting of 983 unrelated white subjects. We then tested the top significant single‐nucleotide polymorphisms (SNPs; 175 SNPs with p < 5 × 10^?4) for replication in a family‐based sample of 2557 white subjects. Combing results from these two samples, we found that two genes, parathyroid hormone (PTH) and interleukin 21 receptor (IL21R), achieved consistent association results in both the discovery and replication samples. The PTH gene SNPs, rs9630182, rs2036417, and rs7125774, achieved p values of 1.10 × 10^?4, 3.24 × 10^?4, and 3.06 × 10^?4, respectively, in the discovery sample; p values of 6.50 × 10^?4, 5.08 × 10^?3, and 5.68 × 10^?3, respectively, in the replication sample; and combined p values of 3.98 × 10^?7, 9.52 × 10^?6, and 1.05 × 10^?5, respectively, in the total sample. The IL21R gene SNPs, rs8057551, rs8061992, and rs7199138, achieved p values of 1.51 × 10^?4, 1.53 × 10^?4, and 3.88 × 10^?4, respectively, in the discovery sample; p values of 2.36 × 10^?3, 6.74 × 10^?3, and 6.41 × 10^?3, respectively, in the replication sample; and combined p values of 2.31 × 10^?6, 8.62 × 10^?6, and 1.41 × 10^?5, respectively, in the total sample. The effect size of each SNP was approximately 0.11 SD estimated in the discovery sample. PTH and IL21R both have potential biologic functions important to bone metabolism. Overall, our findings provide some new clues to the understanding of the genetic architecture of osteoporosis. © 2010 American Society for Bone and Mineral Research     

Delayed short‐course treatment with teriparatide (PTH1–34) improves femoral allograft healing by enhancing intramembranous bone formation at the graft–host junction

Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH_1–34) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40 µg/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40 µg/kg) of PTH_1–34 demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH_1–34 treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2‐week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTH_1–34 were enhanced intramembranous bone formation and remodeling at the graft–host junction. These findings support the potential use of PTH_1–34 as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation. © 2012 American Society for Bone and Mineral Research     

Massive bone reconstruction with heat‐treated bone graft loaded autologous bone marrow‐derived stromal cells and β‐tricalcium phosphate composites in canine models

Bone marrow‐derived stromal cells (BMSCs) contain mesenchymal stem cells that are capable of forming various mesenchymal tissues. We hypothesized that BMSCs and β‐tricalcium phosphate (β‐TCP) composites would promote the remodeling of large‐sized autologous devitalized bone grafts; therefore, the aim of this study was to evaluate the effects of the composites on the remodeling of autologous devitalized bone grafts. Autologous BMSCs cultured in culture medium containing dexamethasone (10^?7 M) were loaded into porous β‐TCP granules under low‐pressure. Theses BMSC/TCP composites were put into the bone marrow cavity of autologous heat‐treated bone (femoral diaphysis, 65‐mm long, 100°C, 30 min) and put back to the harvest site. In the contralateral side, β‐TCP without BMSC were used in the same manner as the opposite side as the control. Treatment with the BMSC/TCP composites resulted in a significant increase in thickness, bone mineral density, and matured bone volume of the cortical bone at the center of the graft compared to the control. Histological analysis showed matured regenerated bone in the BMSC loaded group. These results indicate that BMSC/TCP composites facilitated bone regeneration and maturation at the graft site of large‐sized devitalized bone. This method could potentially be applied for clinical use in the reconstruction of large bone defects such as those associated with bone tumors. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1308–1316, 2013

     

Functionally deficient mesenchymal stem cells reside in the bone marrow niche with M2‐macrophages and amyloid‐β protein adjacent to loose total joint implants

We sought to demonstrate whether there is a difference in the local mesenchymal stem cells (MSC) niche obtained from patients undergoing their first total joint replacement surgery versus those patients undergoing a revision surgery for an failing total joint implant. Bone marrow aspirates collected from patients undergoing revision total joint arthroplasty were observed to be less clonal and the expression of PDGFRα, CD51, ALCAM, endoglin, CXCL12, nestin, and nucleostemin were decreased. Revision MSC were also less able to commit to an osteoblast‐lineage or an adipocyte‐lineage. Further, in revision MSC, OPG, and IL6 expression were increased. Monocytes, derived from revision whole marrow aspirates, were less capable of differentiating into osteoclasts, the cells implicated in the pathologic degradation of bone. Osteoclasts were also not observed in tissue samples collected adjacent to the implants of revision patients; however, the alternatatively activated M2‐macrophage phenotype was observed in parallel with pathologic accumulations of amyloid‐β, τ‐protien and 3‐nitrotyrosine. Despite the limited numbers of patients examined, our data suggest that nucleostemin may be a useful functional marker for MSC while the observation of M2‐macrophage infiltration around the implant lays the foundation for future investigation into a novel mechanism that we propose is associated with loose total joint implants. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:615–624, 2014.     

Use of G‐CSF‐stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review

Chang Y‐J, Huang X‐J. Use of G‐CSF‐stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.
Clin Transplant 2011: 25: 13–23. © 2010 John Wiley & Sons A/S. Abstract: In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony‐stimulating factor (G‐CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen‐matched or haploidentical transplant settings, available data have established the safety of using G‐CSF‐stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G‐CSF‐primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft‐versus‐host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G‐CSF‐stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation.     

Platelet‐rich plasma (PRP) impairs the craniofacial bone repair associated with its elevated TGF‐β levels and modulates the co‐expression between collagen III and α‐smooth muscle actin

Transforming growth factor‐β (TGF‐β) is considered the main inducer of both the α‐smooth muscle actin (α‐SMA) phenotype and collagen synthesis and deposition and plays a significant role in the tissue repair and the development of fibrosis. Since the PRP constitutes an important source of TGF‐β and its efficacy on the craniofacial bone repair remains controversy, the aim of this study was to evaluate the effect of PRP in the presence of levels of TGF‐β on PRP samples, as well as in the presence of collagen III and α‐SMA+ cells, while comparing these results by means of a histomorphometric analysis of the bone matrix and fibrous deposition on the bone repair. Four bone defects of 16 mm² were created on the calvarium of 21 rabbits. The surgical defects were treated with either particulate autograft, particulate autograft mixed with PRP and PRP alone. Animals were euthanized at 15, 30, and 45 days postoperative. Histomorphometric and immunohistochemical analyses were performed to assess repair time, as well as the expression of collagen III, and α‐SMA. The histomorphometric results demonstrated intensive deposition of fibrous tissue while hinder bone deposition occurred in PRP groups. These results coincided with higher values of the TGF‐β on the PRP sample, also larger occurrence of diffuse collagen III deposition and higher presence of α‐SMA+ cells spread among the fibrous tissue. Thus, the higher levels of TGF‐β associated with the both expression of collagen III and α‐SMA on defect treated with PRP suggest that its biomaterial induce an effect that can be considered similarly to a fibroproliferative disorder. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:457–463, 2011     

Repair of rat calvarial defects using Si‐doped hydroxyapatite scaffolds loaded with a bone morphogenetic protein‐2‐related peptide

Tissue engineering promises therapies ideal for treating conventional large bone injuries and defects. In the present study, we developed a novel Si‐HA scaffold loaded with a synthetic BMP‐2‐related peptide, P28, and tested its ability to repair a critical‐sized calvarial defect. We created a calvarial defect (5 mm in diameter) in the parietal bone of 32 rats and implanted one of the following biomaterials: No implant (control), Si‐HA, P28/Si‐HA, or rhBMP‐2/Si‐HA. As assessed by micro CT imaging and histological evaluations, the P28/Si‐HA scaffold promoted bone recovery to a similar degree as the rhBMP‐2/Si‐HA scaffold. In addition, both P28/Si‐HA and rhBMP‐2/Si‐HA promoted recovery better than Si‐HA alone. The novel P28/Si‐HA scaffold might represent a promising biomaterial for future bone tissue engineering applications. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1874–1882, 2016.     

Favourable effect of β‐glucan treatment against cisplatin‐induced reproductive system damage in male rats

The aim of this study was to investigate the potential beneficial effects of β‐glucan treatment against oxidative, histological and spermatological damage caused by cisplatin on the male reproductive system. Twenty‐eight Sprague Dawley male rats were used in the study. The rats were randomly divided into four equal‐sized groups: a control group, cisplatin group (7 mg/kg in a single‐dose cisplatin administered intraperitoneally), β‐glucan group (β‐glucan given at a dose of 50 mg kg^?1 d^?1 for 14 day) and a cisplatin plus β‐glucan group (cisplatin and β‐glucan administered together at the same dose). Cisplatin administration induced an increase in the level of thiobarbituric acid‐reactive substances, a lipid peroxidation indicator. It induced a decrease in enzymatic (superoxide dismutase, catalase and glutathione peroxidase) activities and nonenzymatic (reduced glutathione) antioxidant levels. In addition, cisplatin caused both histological and spermatological damage, as shown by a decrease in sperm motility and epididymal sperm concentrations and an increase in abnormal sperm rates. The β‐glucan treatment improved cisplatin‐induced oxidative, histological and spermatological damage. This study revealed that β‐glucan treatment provided prevention against male reproductive system damage caused by cisplatin. These preventative effects were likely due to its antioxidant properties.     

Combined treatment with a β3‐adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats

Aims

This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β₃‐adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs).

Methods

Thirty‐two female 10‐week‐old SHRs were fed an 8% NaCl‐supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β₃‐ARs and M₃‐MRs expressed within the urinary bladders were analyzed.

Results

Just after transfer from RT to LT, vehicle‐, solifenacin‐, and mirabegron‐treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress‐induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination‐treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M₃‐MR and β₃‐AR mRNA. The tissue distribution of M₃‐MRs was similar to that of the β₃‐ARs.

Conclusions

This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress‐induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026–1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.     

Intraarticular injection autologous platelet‐rich plasma and bone marrow concentrate in a goat osteoarthritis model

To evaluate the effects of intraarticular injections of autologous platelet‐rich plasma (PRP) or bone marrow concentrate (BMC) on osteoarthritis (OA), 24 adult goats were equally divided into control (Ctrl), saline (NS), PRP, and BMC groups, and OA was induced by surgery in NS, PRP, and BMC groups. Autologous PRP and BMC were obtained from whole blood and bone marrow aspirates, respectively. The data revealed, platelets were increased in BMC by 1.8‐fold, monocytes by 5.6‐fold, TGF‐β1 by 7.7‐fold, and IGF‐1 by 3.6‐fold (p < 0.05), and platelets were increased in PRP by 2.9‐fold, and TGF‐β1 by 3.3‐fold (p < 0.05). From the sixth week post‐operation, saline, PRP, and BMC were administered by intraarticular injection once every 4 weeks, three consecutive times. After the animals were sacrificed, inflammatory cytokines in the synovial fluid was measured, and bone and cartilage degeneration progression was observed by macroscopy, histology, and immunohistochemistry. Compared with the NS group, the level of inflammatory cytokines was reduced in the PRP and BMC groups (p < 0.05). Histologically, delayed cartilage degeneration and higher levels of extracellular matrix (ECM) were observed in both PRP and BMC treated groups (p < 0.05). Furthermore, the BMC group showed greater cartilage protection and less ECM loss than the PRP group (p < 0.05). In summary, this study showed that intraarticular injection of autologous PRP and BMC has therapeutic efficacy in a goat osteoarthritis model, with the greater benefit in terms of cartilage protection being observed in the BMC‐treated group than PRP. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2140–2146, 2018.

     

Material properties of bone in the femoral head treated with ibandronate and BMP‐2 following ischemic osteonecrosis

Bone morphogenetic protein (BMP)‐2 and ibandronate (IB) decrease the femoral head deformity following ischemic osteonecrosis of the femoral head (ONFH). The purpose of this study was to determine the effects of BMP‐2 and IB on the mineral content and nanoindentation properties of the bone following ONFH. ONFH was surgically induced in the femoral head of piglets. There were five groups: normal control, untreated, IB, BMP, and BMP + IB (n = 5/group). Backscattered electron imaging, Raman spectroscopy, and nanoindentation testing were performed. Both BMP and BMP + IB groups showed calcium content in the trabecular bone similar to the normal group, while the IB and no‐treatment groups showed a significant increase in the calcium content compared to the normal group. The carbonate content relative to phosphate was significantly increased in the IB and BMP + IB groups (p < 0.01) compared to the normal group. No significant difference was found between the BMP and the normal group. The nanoindentation modulus of the bone in the IB group was significantly increased compared to the normal group (p < 0.05). No significant differences were observed between the BMP and BMP + IB groups compared to the normal group. The nanoindentation hardness measurements in the IB group were also significantly increased compared to the BMP and BMP + IB groups (p < 0.05). In summary, trabecular bone treated with BMP or BMP + IB had material properties comparable to normal bone whereas the bone in the IB group retained the increased mineral content and the nanoindentation hardness found in the necrotic bone. Hence, BMP or BMP + IB better restores the normal mineral content and nanomechanical properties after ONFH than IB treatment alone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1453–1460, 2017.

     

Plasticizer di(2‐ethylhexyl)phthalate interferes with osteoblastogenesis and adipogenesis in a mouse model

Plasticizer di(2‐ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis, and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2‐ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose‐dependently decreased by DEHP and MEHP (10–100 µM) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin (OCN), Wnt1, and β‐catenin were significantly decreased in DEHP‐ and MEHP‐treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARγ mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated β‐catenin/β‐catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARγ inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP‐treated mice, osteoblastogenesis and Runx2, Wnt1, and β‐catenin expression were decreased, but adipogenesis and PPARγ expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/β‐catenin‐regulated and thus triggering bone loss. PPARγ signaling may play an important role in MEHP‐ and DEHP‐induced suppression of osteogenesis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1124–1134, 2018.

     

Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt/β‐catenin signaling in mice

Trabecular bone and cortical bone have different bone remodeling levels, and the underlying mechanisms are not fully understood. In the present study, the expression of Wnt/β‐catenin signaling and its downstream molecules along with bone mass in trabecular and cortical bone were compared in wild‐type mice, constitutive activation of β‐catenin (CA‐β‐catenin) mice and β‐catenin deletion mice. It was found that the expression level of most of the examined genes such as Wnt3a, β‐catenin, osteocalcin and RANKL/OPG ratio were significantly higher in trabecular bone than in cortical bone in wild‐type mice. CA‐β‐catenin resulted in up‐regulated expression of the above‐mentioned genes except for RANKL/OPG ratio, which were down‐regulated. Also, CA‐β‐catenin led to increased number of osteoblasts, decreased number of osteoclasts and increased bone mass in both the trabecular bone and cortical bone compared with wild‐type mice; however, the extent of changes was much greater in the trabecular bone than in the cortical bone. By contrast, null β‐catenin led to down‐regulated expression of the above‐mentioned genes except for RANKL/OPG ratio. Furthermore, β‐catenin deletion led to decreased number of osteoblasts, increased number of osteoclasts and decreased bone mass when compared with wild‐type mice. Again, the extent of these changes was more significant in trabecular bone than cortical bone. Taken together, we found that the expression level of Wnt/β‐catenin signaling and bone remodeling‐related molecules were different in cortical bone and trabecular bone, and the trabecular bone was more readily affected by changes in the Wnt/β‐catenin signaling pathway. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:812–819, 2017.