Development of Functional Interactions Among Cortical and Trabecular Traits During Growth of the Lumbar Vertebral Body

Variation in bone traits that contribute to increased fracture risk in the elderly is mainly established in adulthood. Previous studies have shown that in adults, cortical and trabecular traits are functionally related. How variations in traits develop to establish mechanical function in adult bone is not well understood. In this study, we examined temporal changes in the development of cortical and trabecular traits during growth in mouse lumbar vertebral body structures that have a wide range of genetic variants. We determined a sequence of events among traits that would suggest how functional bone structures developed. Examining bones in A/J, C57/BL6 and C3H/HeJ inbred mouse strains during postnatal growth, we identified inter-strain variation in trabecular architectural traits as seen in adult strains were established by 1 week of age while inter-strain variation in cortical area largely occurred after 4 weeks of age. Across a panel of 20 AXB/BXA Recombinant Inbred mouse strains, we observed a similar sequence in trait development from 4 weeks of age to 16 weeks of age. In addition, the alignment of trabeculae was shown to be a primary variant relative to bone size at an early age. Vertebral bodies that tended to show a large increase in trabecular alignment from 4 weeks of age to 16 weeks of age tended to show a small increase in cortical area over time. However, load borne on the trabecular bone region from 4 weeks of age despite trabecular alignment was important for mechanical stiffness and strength throughout growth. The interaction of anisotropy and bone size in conjunction with the interaction between load sharing and trabecular bone volume at an early age suggested predictive patterns in how traits changed over time relative to bone size. Together these results have great clinical significance because they provide a novel way of assessing mechanical function of the skeletal system by means of coordination of traits and benefit development of predictive models of fracture risk in humans. Understanding the interaction of corticocancellous traits during growth has important implications for genetic analyses and for interpreting the response of bone to genetic and environmental perturbations

Moving toward a prevention strategy for osteoporosis by giving a voice to a silent disease

Abstract A major unmet challenge in developing preventative treatment programs for osteoporosis is that the optimal timing of treatment remains unknown. In this commentary we make the argument that the menopausal transition (MT) is a critical period in a woman’s life for bone health, and that efforts aimed at reducing fracture risk later in life may benefit greatly from strategies that treat women earlier with the intent of keeping bones strong as long as possible. Bone strength is an important parameter to monitor during the MT because engineering principles can be applied to differentiate those women that maintain bone strength from those women that lose bone strength and are in need of early treatment. It is critical to understand the underlying mechanistic causes for reduced strength to inform treatment strategies. Combining measures of strength with data on how bone structure changes during the MT may help differentiate whether a woman is losing strength because of excessive bone resorption, insufficient compensatory bone formation, trabeculae loss, or some combination of these factors. Each of these biomechanical mechanisms may require a different treatment strategy to keep bones strong. The technologies that enable physicians to differentially diagnose and treat women in a preventive manner, however, have lagged behind the development of prophylactic treatments for osteoporosis. To take advantage of these treatment options, advances in preventive treatment strategies for osteoporosis may require developing new technologies with imaging resolutions that match the pace by which bone changes during the MT and supplementing a woman's bone mineral density (BMD)-status with information from engineering-based analyses that reveal the structural and material changes responsible for the decline in bone strength during the menopausal transition.http://deepblue.lib.umich.edu/bitstream/2027.42/134529/1/40695_2016_Article_16.pd

The Role of Scleraxis in Fate Determination of Mesenchymal Stem Cells for Tenocyte Differentiation

Mesenchymal stem cells (MSCs) are pluripotent cells that primarily differentiate into osteocytes, chondrocytes, and adipocytes. Recent studies indicate that MSCs can also be induced to generate tenocyte-like cells; moreover, MSCs have been suggested to have great therapeutic potential for tendon pathologies. Yet the precise molecular cascades governing tenogenic differentiation of MSCs remain unclear. We demonstrate scleraxis, a transcription factor critically involved in embryonic tendon development and formation, plays a pivotal role in the fate determination of MSC towards tenocyte differentiation. Using murine C3H10T1/2 pluripotent stem cells as a model system, we show scleraxis is extensively expressed in the early phase of bone morphogenetic protein (BMP)-12-triggered tenocytic differentiation. Once induced, scleraxis directly transactivates tendon lineage-related genes such as tenomodulin and suppresses osteogenic, chondrogenic, and adipogenic capabilities, thus committing C3H10T1/2 cells to differentiate into the specific tenocyte-like lineage, while eliminating plasticity for other lineages. We also reveal that mechanical loading-mediated tenocytic differentiation follows a similar pathway and that BMP-12 and cyclic uniaxial strain act in an additive fashion to augment the maximal response by activating signal transducer Smad8. These results provide critical insights into the determination of multipotent stem cells to the tenocyte lineage induced by both chemical and physical signals

BMP-12 Treatment of Adult Mesenchymal Stem Cells In Vitro Augments Tendon-Like Tissue Formation and Defect Repair In Vivo

We characterized the differentiation of rat bone marrow-derived mesenchymal stem cells (BM-MSCs) into tenocyte-like cells in response to bone morphogenetic protein-12 (BMP-12). BM-MSCs were prepared from Sprague-Dawley rats and cultured as monolayers. Recombinant BMP-12 treatment (10 ng/ml) of BM-MSCs for 12 hours in vitro markedly increased expression of the tenocyte lineage markers scleraxis (Scx) and tenomodulin (Tnmd) over 14 days. Treatment with BMP-12 for a further 12-hour period had no additional effect. Colony formation assays revealed that ∼80% of treated cells and their progeny were Scx- and Tnmd-positive. BM-MSCs seeded in collagen scaffolds and similarly treated with a single dose of BMP-12 also expressed high levels of Scx and Tnmd, as well as type I collagen and tenascin-c. Furthermore, when the treated BM-MSC-seeded scaffolds were implanted into surgically created tendon defects in vivo, robust formation of tendon-like tissue was observed after 21 days as evidenced by increased cell number, elongation and alignment along the tensile axis, greater matrix deposition and the elevated expression of tendon markers. These results indicate that brief stimulation with BMP-12 in vitro is sufficient to induce BM-MSC differentiation into tenocytes, and that this phenotype is sustained in vivo. This strategy of pretreating BM-MSCs with BMP-12 prior to in vivo transplantation may be useful in MSC-based tendon reconstruction or tissue engineering

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Differential Adaptive Response of Growing Bones From Two Female Inbred Mouse Strains to Voluntary Cage‐Wheel Running

The phenotypic response of bones differing in morphological, compositional, and mechanical traits to an increase in loading during growth is not well understood. We tested whether bones of two inbred mouse strains that assemble differing sets of traits to achieve mechanical homeostasis at adulthood would show divergent responses to voluntary cage‐wheel running. Female A/J and C57BL6/J (B6) 4‐week‐old mice were provided unrestricted access to a standard cage‐wheel for 4 weeks. A/J mice have narrow and highly mineralized femora and B6 mice have wide and less mineralized femora. Both strains averaged 2 to 9.5 km of running per day, with the average‐distance run between strains not significantly different (p = 0.133). Exercised A/J femora showed an anabolic response to exercise with the diaphyses showing a 2.8% greater total area (Tt.Ar, p = 0.06) and 4.7% greater cortical area (Ct.Ar, p = 0.012) compared to controls. In contrast, exercised B6 femora showed a 6.2% (p < 0.001) decrease in Tt.Ar (p < 0.001) and a 6.7% decrease in Ct.Ar (p = 0.133) compared to controls, with the femora showing significant marrow infilling (p = 0.002). These divergent morphological responses to exercise, which did not depend on the daily distance run, translated to a 7.9% (p = 0.001) higher maximum load (ML) for exercised A/J femora but no change in ML for exercised B6 femora compared to controls. A consistent response was observed for the humeri but not the vertebral bodies. This differential outcome to exercise has not been previously observed in isolated loading or forced treadmill running regimes. Our findings suggest there are critical factors involved in the metabolic response to exercise during growth that require further consideration to understand how genotype, exercise, bone morphology, and whole‐bone strength interact during growth. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144252/1/jbm410032.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144252/2/jbm410032_am.pd

Enhanced cell alignment following BMP-12-treatment of scaffolds seeded with BM-MSCs.

<p>Rat BM-MSCs were cultured and implanted as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017531#pone-0017531-g002" target="_blank">Fig. 2</a>. (<b>A</b>) Toluidine blue staining (20X magnification) revealed increased cell elongation and cellular alignment/organization, within the BMP-12-treated BM-MSCs implants. (<b>B</b>) Nuclear aspect ratio (width <i>vs</i> length of nucleus), and (<b>C</b>) Angular deviation (angle between individual nuclear axis and longitudinal axis based on general alignment). A smaller value of nuclear aspect ratio and nuclear orientation angle indicated greater cellular elongation and alignment in cells treated with BMP-12, as compared to untreated cells. * represents p<0.05.</p

Effect of BMP-12 on Scx and Tnmd protein expression in colonies derived from rat BM-MSCs.

<p>Colony forming assays were performed on untreated cells, or on cells treated with BMP-12 for 12 h (“1-hit”) or for 12 h + 12 h. Total, Scx-positive and Tnmd-positive colonies were counted on Day 14 after plating. Data are presented as mean ± S.D. (n = 6); * represents P<0.05 for BMP-12 treated cells compared to untreated controls.</p