New Shunosaurus (Dinosauria: Sauropoda) material from the middle Jurassic lower Shaximiao Formation of Yunyang, Chongqing, China

AUTHORS

Qingyu Ma, Hui Dai,Chao Tan, Ning Li, Ping Wang, Xinxin Ren, Li Meng, Qi Zhao, Guangbiao Wei & Xing Xu

ABSTRACT

Shunosaurus is a small eusauropod from China. It is characterised by solid cervical and dorsal vertebral centra without complicated pneumatic structures, platycoelous or amphicoelous middle and posterior vertebrae and a lack of pubic foramen in adult individuals. Although many Shunosaurus individuals have been discovered, the ontogenetic characteristics of its long bones and bone tissues are not very clear and the existing description of the postcranial skeleton is relatively rudimentary. The new well-preserved and the smallest Shunosaurus specimen discovered in Yunyang, Chongqing, China, provides good material for solving these problems. The radial distal breadth is more than twice the minimum midshaft breadth, and the fibular distal end is twice as wide as the midshaft, while these ratios are all smaller in adult specimens. The lateral trochanter is undeveloped. This individual does show a pubic foramen. The degree of vascularisation of the bone tissue in the juvenile bone tissue is higher for adults. There are no arrested growth lines and peripheral rest lines in the compact bone, indicating that body size still increases slowly after maturity. The discovery of this new material expands the distribution range of Shunosaurus in China.

Injectable sericin based nanocomposite hydrogel for multi-modal imaging-guided immunomodulatory bone regeneration

AUTHORS

Li-Bo Jiang, Sheng-Long Ding, Wang Ding, Di-Han Su, Fang-Xue Zhang, Tai-Wei Zhang, Xiao-Fan Yin, Lan Xiao, Yu-Lin Li, Feng-Lai Yuan, Jian Dong

ABSTRACT

Irregular bone defects, where the inflammation and immune microenvironment confronted with implanted biomaterials, remain a prominent challenge for bone regeneration. In this study, we fabricated an injectable alginate/sericin/graphene oxide (Alg/Ser/GO) hydrogel based on the Alg–Tyramine framework with HRP/H2O2 enzymatic crosslinking. This hydrogel exhibited bioimaging property and controlled degradation behavior upon releasing sericin and GO. Importantly, synergistic effects on bone regeneration between sericin and GO were demonstrated. GO significantly enhanced the spreading, osteogenic differentiation, and mineralization of encapsulated rat BMSCs, whereas the released sericin promoted M2 polarization and migration via the NF-κB and MAPK pathways. The M2 polarization of macrophages induced osteogenic differentiation of BMSCs via several secreted cytokines. Both in vivo and in vitro experiments showed that the Alg/Ser/GO hydrogel induced macrophage infiltration into the surrounding tissues and inhibited inflammation and fibrous capsule thickening. Last, the injected Alg/Ser/GO hydrogels with BMSCs promptly repaired established distal femoral defects in rats. Therefore, the fabricated Alg/Ser/GO hydrogel, along with macrophages and BMSCs, is a promising biomaterial for bone healing, especially the irregular bone defects.

Development of bioinks for 3D printing microporous, sintered calcium phosphate scaffolds

AUTHORS

Sergio A. Montelongo, Gennifer Chiou, Joo L. Ong, Rena Bizios & Teja Guda

ABSTRACT

Beta-tricalcium phosphate (β-TCP)-based bioinks were developed to support direct-ink 3D printing-based manufacturing of macroporous scaffolds. Binding of the gelatin:β-TCP ink compositions was optimized by adding carboxymethylcellulose (CMC) to maximize the β-TCP content while maintaining printability. Post-sintering, the gelatin:β-TCP:CMC inks resulted in uniform grain size, uniform shrinkage of the printed structure, and included microporosity within the ceramic. The mechanical properties of the inks improved with increasing β-TCP content. The gelatin:β-TCP:CMC ink (25:75 gelatin:β-TCP and 3% CMC) optimized for mechanical strength was used to 3D print several architectures of macroporous scaffolds by varying the print nozzle tip diameter and pore spacing during the 3D printing process (compressive strength of 13.1 ± 2.51 MPa and elastic modulus of 696 ± 108 MPa was achieved). The sintered, macroporous β-TCP scaffolds demonstrated both high porosity and pore size but retained mechanical strength and stiffness compared to macroporous, calcium phosphate ceramic scaffolds manufactured using alternative methods. The high interconnected porosity (45–60%) and fluid conductance (between 1.04 ×10−9 and 2.27 × 10−9 m4s/kg) of the β-TCP scaffolds tested, and the ability to finely tune the architecture using 3D printing, resulted in the development of novel bioink formulations and made available a versatile manufacturing process with broad applicability in producing substrates suitable for biomedical applications.

RSPO3 is important for trabecular bone and fracture risk in mice and humans

AUTHORS

Karin H. Nilsson, Petra Henning, Maha El Shahawy, Maria Nethander, Thomas Levin Andersen, Charlotte Ejersted, Jianyao Wu, Karin L. Gustafsson, Antti Koskela, Juha Tuukkanen, Pedro P. C. Souza, Jan Tuckermann, Mattias Lorentzon, Linda Engström Ruud, Terho Lehtimäki, Jon H. Tobias, Sirui Zhou, Ulf H. Lerner, J. Brent Richards, Sofia Movérare-Skrtic & Claes Ohlsson

ABSTRACT

With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.

Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells

AUTHORS

TaoSun, Qiaoqiao Shi, Yongzhi Zhang, Chanikarn Power, Camilla Hoesch, Shawna Antonelli, Maren K. Schroeder, Barbara J. Caldarone, Nadine Taudte, Mathias Schenk, Thore Hettmann, Stephan Schilling, Nathan J. McDannold, Cynthia A.Lemere

ABSTRACT

Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, pathogenic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Here, we used focused ultrasound (FUS) with microbubbles to enhance the intravenous delivery of an Fc-competent anti-pGlu3 Aβ monoclonal antibody, 07/2a mAb, across the blood brain barrier (BBB) in an attempt to improve Aβ removal and memory in aged APP/PS1dE9 mice, an Alzheimer's disease (AD)-like model of amyloidogenesis.

First, we demonstrated that bilateral hippocampal FUS-BBB disruption (FUS-BBBD) led to a 5.5-fold increase of 07/2a mAb delivery to the brains compared to non-sonicated mice 72 h following a single treatment. Then, we determined that three weekly treatments with 07/2a mAb alone improved spatial learning and memory in aged, plaque-rich APP/PS1dE9 mice, and that this improvement occurred faster and in a higher percentage of animals when combined with FUS-BBBD. Mice given the combination treatment had reduced hippocampal plaque burden compared to PBS-treated controls. Furthermore, synaptic protein levels were higher in hippocampal synaptosomes from mice given the combination treatment compared to sham controls, and there were more CA3 synaptic puncta labeled in the APP/PS1dE9 mice given the combination treatment compared to those given mAb alone. Plaque-associated microglia were present in the hippocampi of APP/PS1dE9 mice treated with 07/2a mAb with and without FUS-BBBD. However, we discovered that plaque-associated Ly6G+ monocytes were only present in the hippocampi of APP/PS1dE9 mice that were given FUS-BBBD alone or even more so, the combination treatment. Lastly, FUS-BBBD did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment.

Our findings suggest that FUS is a useful tool to enhance delivery and efficacy of an anti-pGlu3 Aβ mAb for immunotherapy either via an additive effect or an independent mechanism. We revealed a potential novel mechanism wherein the combination of 07/2a mAb with FUS-BBBD led to greater monocyte infiltration and recruitment to plaques in this AD-like model. Overall, these effects resulted in greater plaque removal, sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS-BBBD as a noninvasive method to increase the therapeutic efficacy of drugs or biologics in AD patients.

Characterization of Skeletal Phenotype and Associated Mechanisms With Chronic Intestinal Inflammation in the Winnie Mouse Model of Spontaneous Chronic Colitis

AUTHORS

Ahmed Al Saedi, Shilpa Sharma, Ebrahim Bani Hassan, Lulu Chen, Ali Ghasem-Zadeh, Majid Hassanzadeganroudsari, Jonathan H Gooi, Rhian Stavely, Rajaraman Eri, Dengshun Miao, Kulmira Nurgali, Gustavo Duque

ABSTRACT

Background

Osteoporosis is a common extraintestinal manifestation of inflammatory bowel disease (IBD). However, studies have been scarce, mainly because of the lack of an appropriate animal model of colitis-associated bone loss. In this study, we aimed to decipher skeletal manifestations in the Winnie mouse model of spontaneous chronic colitis, which carries a MUC2 gene mutation and closely replicates ulcerative colitis. In our study, Winnie mice, prior to the colitis onset at 6 weeks old and progression at 14 and 24 weeks old, were compared with age-matched C57BL/6 controls. We studied several possible mechanisms involved in colitis-associated bone loss.

Methods

We assessed for bone quality (eg, microcomputed tomography [micro-CT], static and dynamic histomorphometry, 3-point bending, and ex vivo bone marrow analysis) and associated mechanisms (eg, electrochemical recordings for gut-derived serotonin levels, real-time polymerase chain reaction [qRT-PCR], double immunofluorescence microscopy, intestinal inflammation levels by lipocalin-2 assay, serum levels of calcium, phosphorus, and vitamin D) from Winnie (6–24 weeks) and age-matched C57BL6 mice.

Results

Deterioration in trabecular and cortical bone microarchitecture, reductions in bone formation, mineral apposition rate, bone volume/total volume, osteoid volume/bone surface, and bone strength were observed in Winnie mice compared with controls. Decreased osteoblast and increased osteoclast numbers were prominent in Winnie mice compared with controls. Upregulation of 5-HTR1B gene and increased association of FOXO1 with ATF4 complex were identified as associated mechanisms concomitant to overt inflammation and high levels of gut-derived serotonin in 14-week and 24-week Winnie mice.

Conclusions

Skeletal phenotype of the Winnie mouse model of spontaneous chronic colitis closely represents manifestations of IBD-associated osteoporosis/osteopenia. The onset and progression of intestinal inflammation are associated with increased gut-derived serotonin level, increased bone resorption, and decreased bone formation.