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Eggs contain bioactive compounds thought to benefit pediatric bone. This cross-sectional study shows a positive link between childhood egg intake and radius cortical bone. If randomized trials confirm our findings, incorporating eggs into children's diets could have a significant impact in preventing childhood fractures and reducing the risk of osteoporosis., Introduction: This study examined the relationships between egg consumption and cortical bone in children., Methods: The cross-sectional study design included 294 9-13-year-old black and white males and females. Three-day diet records determined daily egg consumption. Peripheral quantitative computed tomography measured radius and tibia cortical bone. Body composition and biomarkers of bone turnover were assessed using dual-energy X-ray absorptiometry and ELISA, respectively., Results: Egg intake was positively correlated with radius and tibia cortical bone mineral content (Ct.BMC), total bone area, cortical area, cortical thickness, periosteal circumference, and polar strength strain index in unadjusted models (r = 0.144-0.224, all P < 0.050). After adjusting for differences in race, sex, maturation, fat-free soft tissue mass (FFST), and protein intakes, tibia relationships were nullified; however, egg intake remained positively correlated with radius Ct.BMC (r = 0.138, P = 0.031). Egg intake positively correlated with total body bone mineral density, BMC, and bone area in the unadjusted models only (r = 0.119-0.224; all P < 0.050). After adjusting for covariates, egg intake was a positive predictor of radius FFST (β = 0.113, P < 0.050) and FFST was a positive predictor of Ct.BMC (β = 0.556, P < 0.050) in path analyses. There was a direct influence of egg on radius Ct.BMC (β = 0.099, P = 0.035), even after adjusting for the mediator, FFST (β = 0.137, P = 0.020). Egg intake was positively correlated with osteocalcin in both the unadjusted (P = 0.005) and adjusted (P = 0.049) models., Conclusion: If the positive influence of eggs on Ct.BMC observed in this study is confirmed through future randomized controlled trials, whole eggs may represent a viable strategy to promote pediatric bone development and prevent fractures.

The otic and pterygopalatine ganglia are located close to the greater wing (alisphenoid) of the sphenoid bone and many researchers have noted nerves connecting these ganglia in human embryos. The greater wing (alisphenoid) arises from the cartilaginous ala temporalis independently of the lesser wing, but no topographical changes between this cartilage and nerve elements have been demonstrated. We examined histological sections of 20 human embryos and fetuses from 6 to 15 weeks of development (WD). At 6 WD, the ala temporalis, the alar process and ganglia were all identified as a single, undifferentiated cell mass. Subsequently, the two ganglia became identifiable, but were continuous on the superior side of the initial ala temporalis. The temporal, superior spine of the ala temporalis was surrounded by the part that connected the ganglia. At 7 WD, the superior spine of the ala temporalis was reduced in size and the continuity of these ganglia was lost. At this point, a secondarily-formed communicating branch between the ganglia, the nervus sphenoidalis was first identifiable. At 9 WD, the ala temporalis and the alar process had clearly become cartilages, and the anterior end of the otic ganglion was separated from the ala temporalis. The nervus sphenoidalis became longer. At 15 WD, the otic and pterygopalatine ganglia were clear separated from the alisphenoid, which consisted of the cartilaginous ala temporalis and membranous bone. Consequently, the separation between the otic and pterygopalatine ganglia seemed to be due to the developing ala temporalis. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Background: Skeletal development is a complicated process. The status of vitamin D (VD) is closely related to fetal bone development in the embryonic period. Recently, miRNAs have been found to participate in the regulation of skeletal growth and development in several species. However, the mechanisms underlying the interactions among vitamin D, its receptor (VDR), and miRNAs during the process of bone development remain unclear. The aim of this study was to identify miRNAs that are regulated by 1,25(OH) 2 D 3 in murine osteoblasts and to analyze the relationship and the effects of VD/VDR and miRNAs in vitro and in vivo., Methods: We performed miRNA sequencing in murine primary osteoblasts and in an osteoblast cell line treated with 1,25(OH) 2 D 3 to identify miRNAs in these cells. After qRT-PCR validation, miR-140-5p was selected for further analysis. We assessed the pathways comprising predicted target genes for several expressed miRNAs, including miR-140-5p, validated predicted target genes in the MAPK pathway by qRT-PCR, and explored the correlation between VD/VDR and miR-140-5p in vitro and in vivo., Results: 88 miRNAs in murine primary osteoblasts and 49 miRNAs in osteoblast cell line were found to be differentially expressed. MiR-140-5p was upregulated in these 2 types of murine osteoblasts. The expression of miR-140-5p was promoted by 1,25(OH) 2 D 3 through transcriptional activation by VDR, with targeted inhibition of MAPK signaling in osteoblasts. A positive correlation between vitamin D/VDR and miR-140-5p was observed in VDR-knockout mice and in 165 human serum specimens. These data show for the first time that VDR transcriptionally activates miR-140-5p. Therefore, the VD/VDR/miR-140-5p/MAPK signaling axis plays an important role in transmitting the effects of 1,25(OH) 2 D 3 ., Conclusion: Our results demonstrate a novel regulatory mechanism by which miR-140-5p targets the MAPK pathway by means of VD/VDR in vitro and in vivo. These findings provide a new reference for mechanistic research and therapeutic approaches for vitamin D-related bone diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Dexamethasone is routinely used for treating those mothers at risk for preterm delivery. However, overexposure to exogenous glucocorticoids induces bone loss in offspring, and the "critical window" and safe dose of this treatment are largely unknown. In this study, we found that femoral length, and the length of the primary ossification center were significantly reduced in fetal mice after repeated prenatal dexamethasone exposure (PDE). Compared with single-course exposure on gestational day (GD)15, newborn mice with repeated PDE (3 times, from GD15 to 17) showed a significant decrease in femoral trabecular bone mass with decreased trabecular number and thickness. For those newborn mice treated after repeated PDE at different doses (0, 0.2, 0.8, and 1.2 mg/kg/d), the toxic effect of dexamethasone on bone development was observed at 0.8 and 1.2 mg/kg/d. More severe retardation in bone development was observed in the fetal mice after PDE at 0.8 mg/kg/d during GD12-14, compared with that during GD15-17. Interestingly, stronger toxic effects were observed in male newborn mice after PDE than were observed in female newborn mice. In conclusion, PDE with multiple course, higher dose, or exposure at an early stage of pregnancy have stronger toxic effects on bone development of fetal mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

During enchondral ossification, mesenchymal cells express genes regulating the intracellular biosynthesis of cholesterol and lipids. Here, we have investigated conditional deletion of Scap or of Insig1 and Insig2 (Scap inhibits intracellular biosynthesis and Insig proteins activate intracellular biosynthesis). Mesenchymal condensation and chondrogenesis was disrupted in mice lacking Scap in mesenchymal progenitors, whereas mice lacking the Insig genes in mesenchymal progenitors had short limbs, but normal chondrogenesis. Mice lacking Scap in chondrocytes showed severe dwarfism, with ectopic hypertrophic cells, whereas deletion of Insig genes in chondrocytes caused a mild dwarfism and shortening of the hypertrophic zone. In vitro studies showed that intracellular cholesterol in chondrocytes can derive from exogenous and endogenous sources, but that exogenous sources cannot completely overcome the phenotypic effect of Scap deficiency. Genes encoding cholesterol biosynthetic proteins are regulated by Hedgehog (Hh) signaling, and Hh signaling is also regulated by intracellular cholesterol in chondrocytes, suggesting a feedback loop in chondrocyte differentiation. Precise regulation of intracellular biosynthesis is required for chondrocyte homeostasis and long bone growth, and these data support pharmacological modulation of cholesterol biosynthesis as a therapy for select cartilage pathologies., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Bone has many functions. It is responsible for protecting the underlying soft organs, it allows locomotion, houses the bone marrow and stores minerals such as calcium and phosphate. Upon damage, bone tissue can efficiently repair itself. However, healing is hampered if the defect exceeds a critical size and/or is in compromised conditions. The isolation or generation of bone-forming progenitors has applicability to skeletal repair and may be used in tissue engineering approaches. Traditionally, bone engineering uses osteochondrogenic stem cells, which are combined with scaffold materials and growth factors. Despite promising preclinical data, limited translation towards the clinic has been observed to date. There may be several reasons for this including the lack of robust cell populations with favourable proliferative and differentiation capacities. However, perhaps the most pertinent reason is the failure to produce an implant that can replicate the developmental programme that is observed during skeletal repair. Pluripotent stem cells (PSCs) can potentially offer a solution for bone tissue engineering by providing unlimited cell sources at various stages of differentiation. In this review, we summarize key embryonic signalling pathways in bone formation coupled with PSC differentiation strategies for the derivation of bone-forming progenitors.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'., (© 2018 The Author(s).)

Objective There is scant research examining the prevalence of thinness in early childhood, despite its potential negative consequences for health and development across the life course. The objective of this study was to assess bone status through measurement of bone mineral density and biochemical bone turnover markers, with special attention paid to carboxylated (c-OC) as well as undercarboxylated (uc-OC) forms of osteocalcin, in the groups of thin and normal-weight children. Design The study included 80 healthy prepubertal children (median age 7.0 years), who were divided (according to Cole's international cutoffs) into 2 subgroups: thin children ( n = 40, body mass index [BMI] = 13.5 kg/m 2 ) and normal-weight children ( n = 40, BMI = 16.1 kg/m 2 ). Bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy x-ray absorptiometry method. Serum concentrations of C-terminal telopeptide of collagen type I (CTX), total osteocalcin (OC), and c-OC, and uc-OC forms of osteocalcin were determined using enzyme-linked immunosorbent assays. Results In thin children, we observed higher levels of bone resorption marker CTX compared with normal-weight peers. Total osteocalcin concentrations were comparable in both groups of children; however, in thin children we observed higher median values of uc-OC (34.40 vs. 29.30 ng/mL, P < 0.05) and similar c-OC levels (25.65 vs. 28.80 ng/mL). The ratio of c-OC to uc-OC was significantly lower ( P < 0.05) in thin than in normal-weight children. Total BMD and BMC were significantly decreased ( P < 0.0001) in thin children compared with normal-weight peers (0.724 ± 0.092 vs. 0.815 ± 0.060 g/cm 2 and 602.7 ± 159.2 vs. 818.2 ± 220.1 g, respectively). Conclusion Increased concentrations of CTX and uc-OC might lead to disturbances in bone turnover and a decrease in bone mineral density in thin children.

Sports-related traumatic injuries in children have increased in tandem with participation in higher level activities. The developing musculoskeletal structures in children are susceptible to unique injuries that vary with location and the stage of skeletal maturation. The imaging evaluation of sports injuries in children presents several unique challenges. The purpose of this article is to educate the reader on injuries unique to the skeletally immature athlete with focus on their imaging evaluation and diagnosis.

Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, injury to individual tissues is followed by local and systemic compensatory mechanisms that allow the damaged tissue to regain normal proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice in which mosaic expression of the cell cycle suppressor p21 is induced in the cartilage cells (chondrocytes) that drive long-bone elongation. By specifically targeting p21 expression to left hindlimb chondrocytes, the right limb serves as an internal control. Unexpectedly, left-right limb symmetry remained normal, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured that body proportions were maintained. The local response entailed hyperproliferation of spared left limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental function and IGF signalling, revealing bone-placenta communication. Therefore, vertebrates, like invertebrates, can mount coordinated local and systemic responses to developmental insults that ensure that normal body proportions are maintained., Competing Interests: The authors have declared that no competing interests exist.

Background: Epiphyseal-preservation surgery for osteosarcoma is an alternative method which has been indicated carefully to selected patients. The tumor-devitalised autograft treated with liquid nitrogen procedure is one of the biological reconstruction method to reconstruct the defect after tumor excision. The limb length discrepancy is usually appeared in children with their growth after limb-sparing surgery. This study was aimed to investigated the growth of residual epiphysis following epiphyseal-preservation surgery for childhood osteosarcoma around the knee joint., Methods: We retrospectively reviewed 12 patients with osteosarcoma who underwent epiphysis preserving tumor excision (8 in distal femur and 4 in proximal tibia) and reconstructed by using tumor-devitalized autograft treated with liquid nitrogen. The mean patient age was 11 (range, 6 to 14) years. The mean follow-up period were 63 (range, 41 to 90) months. Epiphysis transverse growth rate, epiphysis-width discrepancy (EWD) and collapse of epiphysis were evaluated by using pre- and post-operative whole standing leg radiographs. A retrospective chart review was performed to investigate functional outcome, complications and oncological status., Results: The mean growth of epiphysis rate was 12.6% (range, 3.3 to 28.0%) of affected side and 12.7% (range, 3.8 to 28.9%) of contralateral side, mean EWD was 0.1 mm (range, - 1.0 to 1.7 mm), mean LLD was + 26.1 mm (range, + 1 to + 48 mm) and two patients with distal femoral reconstruction underwent limb lengthening of tibia. There was no collapse of the residual epiphysis. The mean MSTS score was 27.7 (range, 18 to 30)., Conclusions: Epiphysis transverse growth was not diminished, and there was absence of epiphyseal collapse even after epiphyseal-preservation surgery in this small series of childhood osteosarcoma around the knee. With careful assessment for epiphyseal tumor involvement, epiphyseal-preservation surgery shall be possible, and could be an alternative method worth considering.

Context: Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth., Objective: To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively., Design and Outcome Measurements: Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones., Results: Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [-2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: -0.765 to -1.145 (P = 0.002)]. L did not affect physiological bone development., Conclusion: Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy.

Presently, biomechanical support therapy for the femoral head has become an important approach in the treatment of early osteonecrosis of the femoral head (ONFH). Previous studies have reported that the titanium metal trabecular bone reconstruction systems (TMTBRS) achieved satisfactory clinical results for the treatment of early femoral head necrosis. Electron beam melting technology (EBMT) is an important branch of 3D printing technology, which enables the construction of an interface that is required for support of bone in-growth. However, the effect of TMTBRS created using EBMT for clinical applications for early ONFH is still unknown. At present, there are no reports on this topic worldwide. The purpose of this study was to assess the safety of a new 3D printed TMTBRS implant and to evaluate its clinical efficacy in early ONFH.Thirty patients who underwent surgery for ONFH were selected. The stages of ONFH were classified according to the Association Research Circulation Osseus (ARCO) classification. They were followed-up and radiological examination was performed at 6, 12, and 24 months post-surgery to assess TMTBRS stability and bone growth in the bone trabecular holder portion surface. To evaluate hip function, postoperative Harris and Visual Analogue Scale (VAS) scores were used.The postoperative Harris score increased significantly and VAS score decreased significantly at the 12-month follow-up compared to the 24-month follow-up, wherein the Harris score declined slightly and the VAS score was slightly elevated with the aggravation of ONFH. With the passage of time, postoperative improvement rates were 100% for IIA, 70% for IIB, and 0% for IIC. Hip-preserving rates were 100% for IIA, 100% for IIB, and 50% for IIC.The effect of TMTBRS treatment for early ONFH in ARCO IIA and ARCO IIB is satisfactory. However, it is not recommended for a relatively large area of necrosis such as in ARCO IIC.

Horses are precocial animals and able to stand and walk within hours after birth. To cope with associated loading, intrauterine bone development has shown to be anticipative. This study provides further insight into the post-natal development of structurally important features of trabecular and subchondral bone of the talus and sagittal ridge of the tibia of warm-blooded horses. In all areas studied, the average bone volume fraction showed a gradual increase over time, which was the result of a significant increase in trabecular thickness, without significant changes in the degree of anisotropy. Similar to the mineralised part of the bone, collagen content, measured as average retardation using polarised light microscopy, increased significantly, but the degree of anisotropy of the collagen type I network did not. At birth, the subchondral bone layer had a more trabecular aspect, gradually changing to an even surface with only a few vascular canals at an age of 2 months. Presented results indicate the necessity for a stronger structure, but not for a different structural design after birth, providing further evidence for anticipatory bone development in the horse. More knowledge about the strategies used to cope with mechanical loading after birth might be helpful in understanding the developmental bone and joint diseases., (© 2018 Blackwell Verlag GmbH.)

Cancer during adolescence increases the risk for bone mass deficiency later in life. Adolescents with cancer must learn to improve their bone health to avoid osteoporosis. In the present cross-sectional study, we developed and tested scales to assess the bone health self-efficacy and beliefs of adolescents with cancer in Taiwan. Test development followed three stages: item generation and scale formatting, examination of content validity, and validation of psychometric properties with a sample of 100 adolescents with cancer. Through the validation process, this research generated the seven-item Bone Health Self-Efficacy Scale and the 13-item Bone Health Belief Scale. Multiple indices demonstrated construct validity. Cronbach's alphas (0.809 and 0.705) demonstrated internal consistency. No items caused a drop in Cronbach's alpha of 10%, all inter-item correlations were <0.800, and the factor loadings for all items reached 0.400, demonstrating item appropriateness. The present study provides initial evidence of the scales' accessibility and feasibility for adolescents with cancer who speak Mandarin. These scales might also help clinical nurses evaluate the effectiveness of bone health education provided to adolescents with cancer., (© 2018 John Wiley & Sons Australia, Ltd.)

Bone is a connective tissue composed of many cell types, including osteoblasts. How bones acquire their unique size and shape during development remains poorly understood. Herein we investigated the molecular and cellular mechanisms of bone morphogenesis in the zebrafish scale by using transgenic lines to enable visualization of specific types of osteoblasts. We demonstrate that the zebrafish scale contains three distinct types of osteoblasts: (i) a monolayer of central osteoblasts along the inner surface of scales; (ii) marginal osteoblasts elongated along the scale edge; and (iii) submarginal osteoblasts located between the central and marginal osteoblast populations. The size of the central osteoblasts increases progressively during development, suggesting that scale growth is mediated primarily by cell growth rather than the recruitment of new osteoblasts. In addition, the total number of central osteoblasts increases in regenerated scales and is correlated with scale size, possibly allowing for the rapid growth of regenerating scales. Moreover, osteoblast proliferation is not detected during regeneration, suggesting that the osteoblasts originate from post-mitotic precursor cells. Sonic hedgehog a (shha) is expressed in the epidermal cells that make contact with the marginal osteoblasts. Pharmacological inhibition of Hedgehog (Hh) signaling during regeneration reduces the number of marginal osteoblasts and interferes with scale growth, indicating that epidermis-derived Shh regulates scale regeneration. Finally, genetic inhibition of Wnt/planar cell polarity (PCP) signaling in the epidermis results in misorientation of scales with regard to the body axis. These results reveal a novel role for the epidermis in the regulation of bone patterning, namely the regeneration of osteoblasts and directional bone growth., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to search for scientific evidence concerning the accuracy of dental development for estimating the pubertal growth spurt., Methods: It was conducted according to the statements of PRISMA. An electronic search was performed in six databases, including the grey literature. The PICOS strategy was used to define the eligibility criteria and only observational studies were selected., Results: Out of 1,416 identified citations, 10 articles fulfilled the criteria and were included in this systematic review. The association between dental development and skeletal maturity was considered strong in seven studies, and moderate in two, although the association with the pubertal growth spurt had been verified in only four articles. According to half of the studies, the tooth that provided the greater association with the ossification centres was the lower canine. The meta-analysis performed also indicated a positive association, being stronger in females [0.725 (0.649-0.808)]. However, when the method used for dental evaluation was considered, it was possible to verify greater correlation coefficients for Nolla [0.736 (0.666-0.814)] than for Demirjian [0.631 (0.450-0.884)], at the boys sample. The heterogeneity test reached high values (Q = 51.00), suggesting a potential bias within the studies., Conclusions: Most of individual studies suggested a strong correlation between dental development and skeletal maturation, although the association with the peakof pubertal growth spurtwas clearly cited only in some of them. However, due to the high heterogeneity found among the studies included in this meta-analysis, a pragmatic recommendation about the use of dental stages is not possible.

GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsα) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsα, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsα activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsα mutant (Gsα-R201H) conditionally upon Cre recombinase (cGsα R201H mice). Gsα-R201H was expressed in cultured bone marrow stromal cells from cGsα R201H mice upon adenoviral-Cre transduction. When crossed with mice in which Cre is expressed in a tamoxifen-regulatable fashion (CAGGCre-ER™), tamoxifen injection resulted in mosaic expression of the transgene in double mutant offspring. We then crossed the cGsα R201H mice with Prx1-Cre mice, in which Cre is expressed in early limb-bud mesenchyme. The double mutant offspring displayed short limbs at birth, with narrow hypertrophic chondrocyte zones in growth plates and delayed formation of secondary ossification center. Consistent with enhanced Gsα signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsα activity during limb development disrupts endochondral ossification and bone growth. Given that Gsα haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsα activity is essential for normal growth plate physiology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Epidemiological research has suggested that birth weights are correlated with adult leg lengths. However, the relationship between prenatal undernutrition (UN) and postnatal leg growth remains controversial. We investigated the effects of UN during early pregnancy on postnatal hindlimb growth and determined whether early embryonic malnutrition affects the functions of postnatal chondrocytes in rats. Undernourished Wistar dams were fed 40% of the daily intake of rats in the control groups from gestational days 5.5-11.5, and femurs, tibias, and trunks or spinal columns were morphologically measured at birth and at 16 weeks of age in control and undernourished offspring of both sexes. We evaluated cell proliferation and differentiation of cultured chondrocytes derived from neonatal tibias of female offspring and determined chondrocyte-related gene expression levels in neonatal epiphysis and embryonic limb buds. Tibial lengths of undernourished female, but not male, offspring were longer at birth and shorter at 16 weeks of age (p < .05) compared with those of control rats. In chondrocyte culture studies, stimulating effects of IGF-1 on cell proliferation (p < .01) were significantly decreased and levels of type II collagen were lower in female undernourished offspring (p < .05). These phenomena were accompanied by decreased expression levels of Col2a1 and Igf1r and increased expression levels of Fgfr3 (p < .05), which might be attributable to the decreased expression of specificity protein 1 (p < .05), a key transactivator of Col2a1 and Igf1r. In conclusion, UN stress during early pregnancy reduces postnatal tibial growth in female offspring by altering the function of chondrocytes, likely reflecting altered expression of gene transactivators., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. Using calvarial suture mesenchymal cells (SMCs) isolated from the fused and unfused sutures of NSC patients, we demonstrate that during SMC differentiation, the level of the autophagosomal marker LC3-II increases as osteogenic differentiation progresses, particularly at differentiation day 7, a stage concurrent with mineralization. In fused SMCs, autophagic induction was more robust than that in unfused SMCs, which consequently led to enhanced mineralized nodule formation. Perturbation of autophagy with rapamycin or wortmannin promoted or inhibited the ossification of SMCs, respectively. Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC.

Transverse lines, called Harris Lines (HL), osteological markers of recovery from growth arrest episodes, are visible in radiograms of recent and Pleistocene fossil bones. Since on the one hand they mark stressful episodes in life, and on the other are mainly used to trace health fluctuations in prehistoric human communities, I used a cave bear population to check if the processes that could affect the specie' condition were in any way reflected in the bone structure. 392 bear bones from Bear Cave in Kletno (collection: Department of Palaeozoology, University of Wrocław), dated as 32 100 ±1300 to >49 000 years BP, were radiologically examined. The bones were found in a non-anatomical position; morphological analysis indicated that they belonged to different individuals. HL shadows were observed on 9 tibiae and 3 radii: 8.8% out of the 59 tibiae and 77 radii and 3.1% of all the bones. At least 3 transverse lines were recognised in those cases; the specimens were histologically examined. The bear individuals in question experienced regular malnutrition periods during their ontogeny. Starvation resulting in growth inhibition involved young individuals, aged 1 to 4 years. Juveniles aged 6 months, i.e. before weaning, or younger, showed no signs of nutritional stress. Starvation periods associated with seasonal food deficit were not long or common and had no significant effect on the development and welfare of the species. This is the first description of the occurrence of transverse lines in the Pleistocene bear.

The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is incompletely understood. We adopted a genome-wide whole tissue approach to establish a Growth Plate Differential Gene Expression Library (GP-DGEL) for fractionated proliferating, pre-hypertrophic, early and late hypertrophic chondrocytes, as an overarching resource for discovery of pathways and disease candidates. De novo motif discovery revealed the enrichment of SOX9 and GLI binding sites in the genes preferentially expressed in proliferating and prehypertrophic chondrocytes, suggesting the potential cooperation between SOX9 and GLI proteins. We integrated the analyses of the transcriptome, SOX9, GLI1 and GLI3 ChIP-seq datasets, with functional validation by transactivation assays and mouse mutants. We identified new SOX9 targets and showed SOX9-GLI directly and cooperatively regulate many genes such as Trps1, Sox9, Sox5, Sox6, Col2a1, Ptch1, Gli1 and Gli2. Further, FOXA2 competes with SOX9 for the transactivation of target genes. The data support a model of SOX9-GLI-FOXA phasic GRN in chondrocyte development. Together, SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon hypertrophy, FOXA competes with SOX9, and control toward terminal differentiation passes to FOXA, RUNX, AP1 and MEF2 factors.

This study proposes the description of the development of the postcranial axial skeleton, including vertebrae, gastralium, ribs, sternum, and interclavicle, in Melanosuchus niger. Six nests were marked and two eggs removed from each nest at 24-hr intervals until hatching. For posthatching evaluation, 30 hatchlings were kept in captivity and one exemplar was euthanized at three-day intervals. Samples were diaphanized using potassium hydroxide (KOH), alizarin red S, and Alcian blue. A routinely generally used method was applied for histological evaluation. It was difficult to define in which vertebrae the development of cartilaginous centers began, but it was possible to observe that this condensation advanced in the craniocaudal direction. The condensation started in the vertebral arches and was visibly stronger in the cervical and dorsal regions, advancing to the lumbar, sacral and, last, to the caudal region. The atlas showed a highly different morphology compared with the other cervical vertebrae, with a short intercenter, two neural arches, and a proatlas. The ossification process began in the body of cervical vertebrae III to VIII and alizarin retention decreased in the last vertebrae, indicating a craniocaudal direction in bone development, similar to cartilage formation. In the histological sections of gastralium and interclavicles of M. niger at several development stages, it was possible to observe that these elements showed intramembranous development. Anat Rec, 301:607-623, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: The Tanner-Whitehouse radius-ulna-short bone protocol (TW2 RUS) for the assessment of skeletal age (SA) is widely used to estimate the biological (skeletal) maturity status of children and adolescents. The scale for converting TW RUS ratings to an SA has been revised (TW3 RUS) and has implications for studies of youth athletes in age-group sports., Objectives: The aim of this study was to compare TW2 and TW3 RUS SAs in an international sample of male youth soccer players and to compare distributions of players by maturity status defined by each SA protocol., Methods: SA assessments with the TW RUS method were collated for 1831 male soccer players aged 11-17 years from eight countries. RUS scores were converted to TW2 and TW3 SAs using the appropriate tables. SAs were related to chronological age (CA) in individual athletes and compared by CA groups. The difference of SA minus CA with TW2 SA and with TW3 SA was used to classify players as late, average, or early maturing with each method. Concordance of maturity classifications was evaluated with Cohen's Kappa coefficients., Results: For the same RUS score, TW3 SAs were systematically and substantially reduced compared with TW2 SAs; mean differences by CA group ranged from - 0.97 to - 1.16 years. Kappa coefficients indicated at best fair concordance of TW2 and TW3 maturity classifications. Across the age range, 42% of players classified as average with TW2 SA were classified as late with TW3 SA, and 64% of players classified as early with TW2 SA were classified as average with TW3 SA., Conclusion: TW3 SAs were systematically lower than corresponding TW2 SAs in male youth soccer players. The differences between scales have major implications for the classification of players by maturity status, which is central to some talent development programs.

The progression of mineral phase deposition in hypertrophic cartilage and periosteal bone matrix was studied in human metacarpals primary ossification centers before vascular invasion began. This study aimed to provide a morphologic/morphometric comparative analysis of the calcification process in cartilage and periosteal osteoid used as models of endochondral ossification. Thin, sequential sections from the same paraffin inclusions of metacarpal anlagen (gestational age between the 20th and 22nd weeks) were examined with light microscopy and scanning electron microscopy, either stained or heat-deproteinated. This process enabled the analysis of corresponding fields using the different methods. From the initial CaPO 4 nucleation in cartilage matrix, calcification progressed increasing the size of focal, globular, randomly distributed deposits (size range 0.5-5 µm), followed by aggregation into polycyclic clusters and finally forming a dense, compact mass of calcified cartilage. At the same time, the early osteoid calcification was characterized by a fine granular pattern (size range 0.1-0.5 µm), which was soon compacted in the layer of the first periosteal lamella. Scanning electron microscopy of heat-deproteinated sections revealed a rod-like hydroxyapatite crystallite pattern, with only size differences between the early globular deposits of the two calcifying matrices. The morphology of the early calcium deposits was similar in both cartilage and osteoid, with variations in size and density only. However, integration of the reported data with the actual hypotheses of the mechanisms of Ca concentration suggested that ion transport was linked to the progression of the chondrocyte maturation cycle (with recall of H 2 O from the matrix) in cartilage, while ions transport was an active process through the cell membrane in osteoid. Other considered factors were the collagen type specificity and the matrix fibrillar texture. Anat Rec, 301:571-580, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Little is known about the relationship between bone fragility and respiratory function. We hypothesized that women with osteoporosis or osteopenia, without cardio-pulmonary disease, have perturbations in the pattern of breathing and gas exchange., Methods: In 44 women with bone fragility (BF, T score: < -1), and 20 anthropomorphically-matched control women (T score > -1) we compared pulmonary function tests, central respiratory drive (mouth occlusion pressure or P 0.1), pattern of breathing using optoelectronic plethysmograph and arterial blood gases at rest., Results: Static pulmonary function was similar in BF subjects and controls. However, the arterial blood gas measurements differed significantly. The arterial pH was significantly higher in BF subjects than in controls (P < 0.001). The partial pressure of carbon dioxide (PaCO 2 ) and oxygen (PaO 2 ) in arterial blood were significantly lower in BF subjects than controls (P < 0.001 and P = 0.009, respectively). The BF subjects had a shorter inspiratory fraction compared with controls (P = 0.036). Moreover, T-scores were significantly inversely correlated with the alveolar-arterial gradient of oxygen (r = -0.5; P = 0.0003) and the arterial pH (r = -0.4; P = 0.002), and positively correlated with arterial PaO 2 (r = 0.3; P = 0.01) and PaCO 2 (r = 0.4; P = 0.002) among all subjects., Conclusion: In the absence of known cardio-pulmonary disease, BF is associated with statistically significant perturbations in gas exchange and alterations in the pattern of breathing including shortening of the inspiratory time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown. The inhibitory effect of Matk on osteoclasts was closely related with the inhibition of c-Src activity. Intriguingly, Matk overexpression in osteoblasts reduced bone nodule formation. Conversely, Matk knockdown increased osteoblast function. Most importantly, binding of Matk to Runx2 resulted in the inhibition of Runx2 translocation into the nucleus and downregulation of Runx2 target genes. Taken together, our findings demonstrated that Matk plays a critical role in bone metabolism by impairing the functions of osteoclasts and osteoblasts via distinct mechanisms involving inhibition of c-Src-dependent and -independent signaling pathways., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Tissue-nonspecific alkaline phosphatase (TNAP) is playing a key role in bone calcification, as has been demonstrated in different mammalian species including human and rodents. However, to investigate age-related changes during life history, histochemical demonstration of TNAP is severely hampered, particularly in the elderly, by technical difficulties associated with sectioning calcified tissue. Sufficient fixation must precede decalcification since poorly fixed bone tissue is exposed to the deleterious effects of decalcification reagents. In order to find a method that would allow cryosectioning of bone without loss of TNAP activity, we assessed the efficacy of different fixation reagents regarding the effects on structural integrity and TNAP activity using liver and osseous tissue from younger and older horses. The results of this study reveal that glyoxal-based fixatives sufficiently preserved bone tissue for successful cryosectioning without compromising TNAP activity. The method described combines the demonstration of TNAP activity with optimal preservation of tissue morphology in osseous tissue of younger and even of older mammals. As a model species, we selected horse bones in light of potentially higher similarities to ageing history and lifelong locomotion in humans as compared to other, mostly smaller, experimental model species with a much shorter life span and artificial locomotive activity when kept in cages. This may serve as a basis for future studies addressing the impact of different life traits in iconic, domestic and companion animals, which are often patients in veterinary medicine, as well as for basic research on human physiology and pathologies of the musculoskeletal system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Preterm infants are at risk for impaired bone mineralization and growth in length later in life due to inadequate nutritional intake in the early postnatal period., Objective: To investigate whether increased nutritional supplementation of calcium, phosphate and protein in Very Low Birth Weight (VLBW) infants during the first 14days after birth was associated with improvement in length and bone development until 9-10years of age., Design: Observational follow-up study of VLBW infants (birth weight<1500g or gestational age<32weeks) born in two consecutive years (eligible infants: 2004 n: 63 and 2005: n: 66). Cohort 2005 received higher intake of calcium, phosphate and protein with parenteral nutrition compared to Cohort 2004. Anthropometric data were collected during standard follow-up visits until five years, and additionally at 9-10years of age including measurements of bone mineral content, bone mineral density of the whole body and lumbar spine determined by dual-energy X-ray absorptiometry. Long-term growth trajectories of both cohorts were evaluated separately for participants born appropriate (AGA) and small for gestational age (SGA), stratified by gender. Multivariate linear regression was used to examine the effect of nutritional intake and clinical covariates on length and bone mineralization., Results: Both cohorts achieved a catch-up in length to SDS within the normal range by 6months (length SDS: estimated mean (95% confidence interval (CI): 6months: Cohort 2004: -0.7 (-1.1, -0.3) Cohort 2005: -0.5 (-0.8, -0.2)). Bone mineral content and density were within the normal range and not different between the cohorts. SGA children achieved a catch-up in length at 5years with bone mineralization comparable to AGA children. Only for girls birth weight was significantly associated with length SDS (per gram: β 0.001; 95% CI (0.000, 0.003); p=0.03) There was no evidence of an association between early nutritional intake and bone mineralization., Conclusion: Children born as appropriate or small for gestational age preterm infants are able to catch up in length after the postnatal period, and achieve a normal length and bone mineralization at age nine-ten years. An improvement of calcium and phosphate intake during the first 14days after birth was not associated with improvement in length and bone development., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to analyze the effects of soccer practice on bone in male and female children and adolescents. MEDLINE, PubMed, SPORTDiscus and Web of Science databases were searched for scientific articles published up to and including October 2016. Twenty-seven studies were included in this systematic review (13 in the meta-analysis). The meta-analysis was performed by using OpenMeta[Analyst] software. It is well documented that soccer practice during childhood provides positive effects on bone mineral content (BMC) and density (BMD) compared to sedentary behaviors and other sports, such as tennis, weightlifting, or swimming. Furthermore, soccer players present higher BMC and BMD in most weight-bearing sites such as the whole body, lumbar spine, hip, and legs. Moreover, bone differences were minimized between groups during prepuberty. Therefore, the maturity status should be considered when evaluating bone. According to meta-analysis results, soccer practice was positively associated with whole-body BMD either in males (mean difference 0.061; 95%CI, 0.042-0.079) or in females (mean difference 0.063; 95%CI, 0.026-0.099)., Conclusion: Soccer may be considered a sport that positively affects bone mass during growth. Pubertal soccer players presented increased bone mass compared to controls or other athletes; however, these bone differences are minimized during the prepubertal stage. What is known: • It has been described that childhood and adolescence are important periods for bone mass and structure. • Previous studies have demonstrated that soccer participation improves bone mass in male and female children and adolescents. What is new: • The differences between soccer players and controls are more marked during puberty than prepuberty. • Weight-bearing sites such as lumbar spine, hip, femoral neck, trochanter, intertrochanteric region and both legs are particularly sensitive to soccer actions.

Studies suggest bone growth and development are influenced by maternal nutrition, during intrauterine and early postnatal life. This study assessed the role of MGP and a maternal high fat diet on vitamin K-dependent proteins' gene expression and their impact on bone formation. Knockout (KO) offspring were smaller than wild type (WT) littermates, yet possessed the same volume of intrascapular brown adipose tissue. The total proportion of body fat was reduced, but only in animals on a control diet. Lung air volume was observed to be comparable in both KO and WT animals on the same diet. The degree of aortic calcification was reduced in KO animals maintained on a HF diet. KO females on the high fat diet showed reduced cortical bone volume and thickness in the femur and tibia. Gene expression levels of GGCX and VKOR were reduced in control fed KO animals suggesting a potential link between gene expression levels of MGP, GGCX, and VKOR and total volumes of bone, calcified soft tissue, and iBAT; with implications for modulation of body length and mass. Our results confirm the important role for vitamin K in bone and calcified soft tissue, but now extend this role to include iBAT.

Purpose of Review: The purpose of this review is to examine the anorexia nervosa-microbiota-bone relationship, offering a compilation of the relevant human and animal studies that may contribute to a more comprehensive understanding of potential mechanisms involved., Recent Findings: Recent studies have implicated fermentation by-products of the gut microbiota in bone metabolism. Compromised bone health often accompanies anorexia nervosa due to energy deficiency and hypoestrogenism. The gut microbiome has been implicated as a link between these conditions and impaired bone growth phenotypes. Current research supports decrements in Firmicutes and short-chain fatty acids with increases in Methanobrevibacter smithii and Proteobacteria in anorexia nervosa. A potential mechanism for microbiome-regulated bone growth is through modulation of insulin-like growth factor-1. Future research should aim to examine short-chain fatty acids, probiotics, and prebiotics as alternative therapies to treat low bone density in anorexia nervosa.

Background: Chondroblastoma is a rare benign cartilaginous tumor, which primarily occurs in children and adolescents. Chondroblastoma commonly originates in the epiphyseal plate of long bones. An aggressive curettage treatment is recommended to manage lesion, which may jeopardize an open epiphyseal plate and result in limb shortening and deformity as the limb grows and develops. The purpose is to observe surgical effects of chondroblastoma on open epiphyseal plate of long bones in children and adolescents and explore influences on limb growth and development., Methods: We retrospectively reviewed 18 cases of long bone chondroblastoma with open epiphyseal growth plate during March 2004 to October 2010 in our center. Seven females and 11 males with mean age of 11.6 ± 2.0 years old (8-15 years) were included. Patients, who suffered from trauma and pathological fracture of the epiphyseal plate or congenital diseases such as poliomyelitis, congenital dementia, and cartilage malnutrition, were excluded. All patients were treated with meticulous intralesional curettage and inactivity with alcohol followed by bone grafts. All cases were followed up 8.2 ± 1.7 years (5-11.5 years)., Results: All had no local recurrence and distance metastasis. The length of the affected limb was short, 18.47 ± 7.22 mm (1.5-30 mm). There was no obvious relativity with tumor activity (P = 0.061). Meanwhile, there were obvious relativity with the greatest dimension of the lesion (TGD) (P = 0.003), the vertical dimension between edge of lesion and epiphyseal line (TVD) (P = 0.010), and area ratio of lesion to local epiphysis (lesion/growth plate) (P = 0.015). The MSTS93 (Revised Musculoskeletal Tumor Society Rating Scale 93) and SF-36 (Medical Outcomes Study 36-Item Short-Form Health Survey) had been significantly improved (P < 0.01)., Conclusion: Managing of chondroblastoma located in open epiphyseal plate of a long bone with meticulous curettage, inactivity, and bone grafts can control tumor progression and recurrence effectively. Meanwhile, early detection and prompt surgical treatment intervention, which reduced significantly the tumor to influence limb growth and development, get encouraging limb function., Trial Registration: This is a retrospective study, which was not registered in any trial registry.

Objective: Chondrocyte differentiation is crucial for long bone growth. Many cartilage extracellular matrix (ECM) proteins reportedly contribute to chondrocyte differentiation, indicating that mechanisms underlying chondrocyte differentiation are likely more complex than previously appreciated. Angiopoietin-like protein 2 (ANGPTL2) is a secreted factor normally abundantly produced in mesenchymal lineage cells such as adipocytes and fibroblasts, but its loss contributes to the pathogenesis of lifestyle- or aging-related diseases. However, the function of ANGPTL2 in chondrocytes, which are also differentiated from mesenchymal stem cells, remains unclear. Here, we investigate whether ANGPTL2 is expressed in or functions in chondrocytes., Methods: First, we evaluated Angptl2 expression during chondrocyte differentiation using chondrogenic ATDC5 cells and wild-type epiphyseal cartilage of newborn mice. We next assessed ANGPTL2 function in chondrogenic differentiation and associated signaling using Angptl2 knockdown ATDC5 cells and Angptl2 knockout mice., Results: ANGPTL2 is expressed in chondrocytes, particularly those located in resting and proliferative zones, and accumulates in ECM surrounding chondrocytes. Interestingly, long bone growth was retarded in Angptl2 knockout mice from neonatal to adult stages via attenuation of chondrocyte differentiation. Both in vivo and in vitro experiments show that changes in ANGPTL2 expression can also alter p38 mitogen-activated protein kinase (MAPK) activity mediated by integrin α5β1., Conclusion: ANGPTL2 contributes to chondrocyte differentiation and subsequent endochondral ossification through α5β1 integrin and p38 MAPK signaling during bone growth. Our findings provide insight into molecular mechanisms governing communication between chondrocytes and surrounding ECM components in bone growth activities., (Copyright © 2017. Published by Elsevier Ltd.)

Thyroid hormone (TH) is an established regulator of skeletal growth and maintenance both in clinical studies and in laboratory models. The clinical consequences of altered thyroid status on the skeleton during development and in adulthood are well known, and genetic mouse models in which elements of the TH signaling axis have been manipulated illuminate the mechanisms which underlie TH regulation of the skeleton. TH is involved in the regulation of the balance between proliferation and differentiation in several skeletal cell types including chondrocytes, osteoblasts, and osteoclasts. The effects of TH are mediated primarily via the thyroid hormone receptors (TRs) α and β, ligand-inducible nuclear receptors which act as transcription factors to regulate target gene expression. Both TRα and TRβ signaling are important for different stages of skeletal development. The molecular mechanisms of TH action in bone are complex and include interaction with a number of growth factor signaling pathways. This review provides an overview of the regulation and mechanisms of TH action in bone, focusing particularly on the role of TH in endochondral bone formation during postnatal growth., (© 2018 Elsevier Inc. All rights reserved.)

To repair bone defects, we evaluate the in-vitro and in-vivo osteogenic activities of a novel tissue-engineered bone (TEB) by elaborately combining biomimetic calcium phosphate (BioCaP) granules with internally-incorporated simvastatin (SIM) and human adipose-derived stem cells (hASCs). First, we constructed BioCaP with SIM internally incorporated (SIM-BioCaP). Then we characterized the morphology and chemical composition of SIM-BioCaP. The release kinetics of SIM was monitored in vitro spectroscopically. Thereafter, we explored the in-vitro cellular responses of hASCs to SIM-BioCaP by performing scanning electron microscopy observation, proliferation assay, alkaline phosphatase (ALP) activity assay, alizarin red staining and real-time PCR. Finally, we investigated the in-vivo osteogenic activities of the novel TEB in a subcutaneous bone induction model in nude mice. We found that SIM was successfully incorporated internally in BioCaP and showed a slow release manner without significantly affecting the attachment and proliferation of hASCs. The released SIM from BioCaP could significantly enhance the proliferation, ALP activities, mineralized nodules formation and osteogenic genes of hASCs. The in-vivo tests showed this TEB could induce new bone formation while the other groups could not. Taken together, the present data show that this novel TEB represented a very promising construct to treat critical-volume bone defects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Thyroid hormone (TH) is essential for skeletal development from the late fetal life to the onset of puberty. During this large window of actions, TH has key roles in endochondral and intramembranous ossifications and in the longitudinal bone growth. There is evidence that TH acts directly in skeletal cells but also indirectly, specially via the growth hormone/insulin-like growth factor-1 axis, to control the linear skeletal growth and maturation. The presence of receptors, plasma membrane transporters, and activating and inactivating enzymes of TH in skeletal cells suggests that direct actions of TH in these cells are crucial for skeletal development, which has been confirmed by several in vitro and in vivo studies, including mouse genetic studies, and clinical studies in patients with resistance to thyroid hormone due to dominant-negative mutations in TH receptors. This review examines progress made on understanding the mechanisms by which TH regulates the skeletal development., (© 2018 Elsevier Inc. All rights reserved.)

Background: To what extent does the circulating 25-hydroxyvitamin D (25[OH]D) concentration help to meet the physiological needs of humans is an ongoing subject of debate. Remaining unexposed to the sun to reduce melanoma cancer risk, current lifestyle with less out door activities, and increasing obesity rates, which in turn increases the storage of vitamin D in the adipose tissue, are presumably factors that contribute to the substantial upsurge in the prevalence of vitamin D deficiency in humans. Since evidence is lacking regarding the appropriate cut-off points to define vitamin D status during pregnancy, references used to establish the intake recommendations and vitamin D content of prenatal vitamin supplements are quite conservative., Summary: The foetus depends fully on maternal 25(OH)D supply. 25(OH)D readily crosses the placenta and it is activated into 1,25(OH)2D by foetal kidneys. Moreover, 1,25(OH)2D can also be synthesized within the placenta to regulate placental metabolism. The importance of vitamin D during pregnancy for maintaining maternal calcium homeostasis and therefore for foetal bone development is well recognized; major discussions are in progress regarding the potential maternal detrimental effects on pregnancy outcomes, foetal development, and the long-term health of children. Interventional studies have also evaluated the effect of vitamin D for reduction on preterm birth and asthma programming. Key Messages: Clinically, by understanding the effects of vitamin D on perinatal outcomes, we could individualize antenatal counselling regarding vitamin D supplementation to ensure vitamin D repletion without increasing the risk of foetal hypercalcemia., (© 2018 S. Karger AG, Basel.)

Pseudarthrosis is an exceedingly common, costly, and morbid complication in the treatment of long bone fractures and after spinal fusion surgery. Electrical bone growth stimulation (EBGS) presents a unique approach to accelerate healing and promote fusion success rates. Over the past three decades, increased experience and widespread use of EBGS devices has led to significant improvements in stimulation paradigms and clinical outcomes. In this paper, we comprehensively review the literature and examine the history, scientific evidence, available technology, and clinical applications for EBGS. We summarize indications, limitations, and provide an overview of cost-effectiveness and future directions of EBGS technology. Various models of electrical stimulation have been proposed and marketed as adjuncts for spinal fusions and long bone fractures. Clinical studies show variable safety and efficacy of EBGS under different conditions and clinical scenarios. While the results of clinical trials do not support indiscriminate EBGS utilization for any bone injury, the evidence does suggest that EBGS is desirable and cost efficient for certain orthopedic indications, especially when used in combination with standard, first-line treatments. This review should serve as a reference to inform practicing clinicians of available treatment options, facilitate evidence-based decision making, and provide a platform for further research.

The disk of hyaline cartilage that is interposed between the epiphysis and the metaphysis of each of the long bones is responsible for its elongation, and, thus, when the lower limbs are concerned, for increases in bodily height. This so-called growth plate is avascular, aneural, and alymphatic. It consists solely of chondrocytes and an extracellular matrix which the cells elaborate. The growth plate is architectonically striking in so far as the chondrocytes are aligned in strictly vertical columns, which represent the functional units of longitudinal bone growth. The growth process begins with the slow division of chondrocytes in the resting ("stem cell") zone and proceeds with their rapid proliferation in the adjacent zone. These cells then undergo a process of progressive enlargement, which culminates in the zone of terminal hypertrophy. The life history of any given cell is recapitulated in a vertical column. The neoformation of cartilage in the axial direction is synchronized with its destruction at the vascular invasion front of the metaphysis and results in an elongation of the bony trabeculae. The mechanism that governs the highly coordinated sequence of events that underlies the growth of the long bones is complex; it is subject to influence by genetic, hormonal, nutritional, environmental, and pathological factors., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

The emergence of the endochondral skeleton in terrestrial animals enabled ambulation against increased gravitational forces and provided a storage site for scarce minerals essential for life. This skeletal upgrade increased overall fuel requirements and altered global energy balance, prompting the evolution of endocrine networks to coordinate energy expenditure. Bone-forming osteoblasts require a large and constant supply of energy substrates to fuel bone matrix production and mineralization. When fuel demands are unmet, bone quality and strength are compromised. Recent studies suggest that key developmental signaling pathways are coupled to bioenergetic programs, accommodating changes in energy requirements at different stages of the osteoblast life cycle. Studies in genetically altered mice have confirmed a link between bone cells and global metabolism and have led to the identification of hormonal interactions between the skeleton and other tissues. These observations have prompted new questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve treatments for patients with diabetes and osteoporosis., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

Evidence of a periodic biorhythm is retained in tooth enamel in the form of Retzius lines. The periodicity of Retzius lines (RP) correlates with body mass and the scheduling of life history events when compared between some mammalian species. The correlation has led to the development of the inter-specific Havers-Halberg oscillation (HHO) hypothesis, which holds great potential for studying aspects of a fossil species biology from teeth. Yet, our understanding of if, or how, the HHO relates to human skeletal growth is limited. The goal here is to explore associations between the biorhythm and two hard tissues that form at different times during human ontogeny, within the context of the HHO. First, we investigate the relationship of RP to permanent molar enamel thickness and the underlying daily rate that ameloblasts secrete enamel during childhood. Following this, we develop preliminary research conducted on small samples of adult human bone by testing associations between RP, adult femoral length (as a proxy for attained adult stature) and cortical osteocyte lacunae density (as a proxy for the rate of osteocyte proliferation). Results reveal RP is positively correlated with enamel thickness, negatively correlated with femoral length, but weakly associated with the rate of enamel secretion and osteocyte proliferation. These new data imply that a slower biorhythm predicts thicker enamel for children but shorter stature for adults. Our results develop the intra-specific HHO hypothesis suggesting that there is a common underlying systemic biorhythm that has a role in the final products of human enamel and bone growth., (© 2017 Anatomical Society.)

Despite its importance as a key parameter of child health and development, growth velocity is difficult to determine in real time because skeletal growth is slow and clinical tools to accurately detect very small increments of growth do not exist. We report discovery of a marker for skeletal growth in infants and children. The intact trimeric noncollagenous 1 (NC1) domain of type X collagen, the marker we designated as CXM for Collagen X Marker, is a degradation by-product of endochondral ossification that is released into the circulation in proportion to overall growth plate activity. This marker corresponds to the rate of linear bone growth at time of measurement. Serum concentrations of CXM plotted against age show a pattern similar to well-established height growth velocity curves and correlate with height growth velocity calculated from incremental height measurements in this study. The CXM marker is stable once collected and can be accurately assayed in serum, plasma, and dried blood spots. CXM testing may be useful for monitoring growth in the pediatric population, especially responses of infants and children with genetic and acquired growth disorders to interventions that target the underlying growth disturbances. The utility of CXM may potentially extend to managing other conditions such as fracture healing, scoliosis, arthritis, or cancer., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Pediatricians have relied on methods for determining skeletal maturation for >75 years. Bone age continues to be a valuable tool in assessing children's health. New technology for bone age determination includes computer-automated readings and assessments obtained from alternative imaging modalities. In addition, new nonclinical bone age applications are evolving, particularly pertaining to immigration and children's rights to asylum. Given the significant implications when bone ages are used in high-stake decisions, it is necessary to recognize recently described limitations in predicting accurate age in various ethnicities and diseases. Current methods of assessing skeletal maturation are derived from primarily white populations. In modern studies, researchers have explored the accuracy of bone age across various ethnicities in the United States. Researchers suggest there is evidence that indicates the bone ages obtained from current methods are less generalizable to children of other ethnicities, particularly children with African and certain Asian backgrounds. Many of the contemporary methods of bone age determination may be calibrated to individual populations and hold promise to perform better in a wider range of ethnicities, but more data are needed., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Exercise is often recommended as a promising non-pharmacologic countermeasure to prevent osteoporosis. However, elderly osteoporotic patients generally have physical fitness difficulties preventing them from performing effective and sustainable exercise. Electromyostimulation should be one effective modality for non-pharmacological prevention of osteoporosis without any voluntary physical movements. However, successful stimulation patterns remain controversial. As suggested by our previous in vitro studies, randomized timing of stimulation could be a candidate to maximize the osteogenic effect of electromyostimulation. In this study, the effects of random stimulation to the quadriceps on osteogenesis in the femurs were investigated using rats, in comparison with a periodic stimulation pattern. In histomorphometric assessments, both stimulation patterns demonstrated increases in bone formation rate either in cortical bone at the midshaft or in trabecular bone at the femoral neck on the stimulated side. However, maximum load and strain energy to failure were enhanced only by the random stimulation, on either the stimulated or non-stimulated side. It is concluded that randomized muscle stimulation has effective osteogenic capability at the stimulation site, similar to periodic stimulation; however, its effectiveness on mechanical properties is expandable to other non-stimulated sites.

No studies have explored the relationship with maternal vitamin D (25(OH)D) in pregnancy and offspring trabecular bone score (TBS). Our data suggest that maternal 25(OH)D in early pregnancy, but not late, may be associated with offspring TBS in boys. These data act as hypothesis-generating findings for confirmation in larger, longer-term studies., Introduction: Trabecular bone score (TBS), a novel tool derived from dual-energy X-ray absorptiometry (DXA), reflects the microarchitecture of the vertebrae. It has been shown to predict fracture independent of standard DXA parameters in adult populations. Previously, we demonstrated that maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy is associated with offspring bone mineral content at age 11 years. However, associations with TBS have not been explored, thus we aimed to determine associations between maternal 25(OH)D and offspring TBS., Methods: Data were collected from the Vitamin D in Pregnancy (VIP) study. Venous blood samples were taken at recruitment and at 28-32 weeks' gestation. Maternal 25(OH)D was measured by radioimmunoassay. Offspring (n = 195, n = 181 with complete measures) underwent spine DXA (GE Lunar), at age 11 years (median = 10.9 (IQR 10.9-11.4)). TBS was calculated using TBS iNsight software., Results: Offspring of mothers with sufficient 25(OH)D levels (≥50 nmol/L) at recruitment had a higher TBS (1.363 vs. 1.340, p = 0.04). In multivariable linear regression models, after adjustment for child relative lean mass, sex and pubertal stage, a 10 nmol/L increase in maternal 25(OH)D was associated with a 0.005 (95% CI 0.000, 0.010, p = 0.04) increase in TBS. However when stratified by sex (p for interaction = 0.16), the association was significant in boys, but not girls. There were no associations with TBS and maternal 25(OH)D at 28-32 weeks., Conclusions: We speculate that maternal 25(OH)D in early pregnancy may be associated with TBS in offspring at age 11 in boys. These hypothesis-generating findings warrant confirmation with larger interventional and long-term follow-up studies.

During embryogenesis, the musculoskeletal system develops while containing within itself a force generator in the form of the musculature. This generator becomes functional relatively early in development, exerting an increasing mechanical load on neighboring tissues as development proceeds. A growing body of evidence indicates that such mechanical forces can be translated into signals that combine with the genetic program of organogenesis. This unique situation presents both a major challenge and an opportunity to the other tissues of the musculoskeletal system, namely bones, joints, tendons, ligaments and the tissues connecting them. Here, we summarize the involvement of muscle-induced mechanical forces in the development of various vertebrate musculoskeletal components and their integration into one functional unit., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Background: Determination of skeletal maturation and remaining growth potential is an essential part of treatment planning in orthodontics. The aim of our study was to determine the relationship between IGF-1 levels, IGFBP-3 levels with CVM staging to track the pre pubertal and pubertal growth spurts in female patients in North Indian population., Methods: This cross-sectional study was conducted on ninety female subjects in the age group of 8-20 years. Blood samples were collected and centrifuged and serum samples were then analysed by Human IGF-1 and IGFBP-3 enzyme-linked immunosorbent assay kits, specific for IGF-1 and IGFBP-3, respectively. CVM staging on lateral cephalometric radiograph was determined for all patients. Analysis of variance test followed by a post hoc test was used to compare mean IGF-1 and IGFBP-3 corresponding to six stages of cervical vertebrae maturation stages. Linear Pearson's correlations were performed to determine the trends of IGF-1, IGFBP-3, and its ratio relating to CVM stage. The kappa statistic was used to measure inter and intra examiner reliability. P value <0.05 was considered as statistically significant., Results: Mean serum IGF-1 levels were found to be highest (403.3 ± 12.3 ng/ml) at CVMI3 stage of CVMI. The post-hoc test revealed a significant difference in IGF-1 levels between all stages of CVMI, thereby indicating a specific range of IGF-1 levels for a specific skeletal stage. Mean serum IGFBP-3 levels were found to be highest (5186.8 ± 1384.2 ng/ml) at CVMI4 stage of CVMI. The mean serum IGFBP-3 levels at CVMI4 were found to be significantly higher than the levels at all other CVMI stages except CVMI3 stage., Conclusions: IGF-1 and IGFBP-3 can serve as a potential biochemical indicator for assessment of skeletal maturity.

Mesenchymal stem/progenitor cells (MSPCs) undergo rapid self-renewal and differentiation, contributing to fast skeletal growth during childhood and puberty. It remains unclear whether these cells change their properties during late puberty to young adulthood, when bone growth and accrual decelerate. Here we show that MSPCs in primary spongiosa of long bone in mice at late puberty undergo normal programmed senescence, characterized by loss of nestin expression. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3, and deletion of Ezh2 in early pubertal mice results in premature cellular senescence, depleted MSPCs pool, and impaired osteogenesis as well as osteoporosis in later life. Our data reveals a programmed cell fate change in postnatal skeleton and unravels a regulatory mechanism underlying this phenomenon.

Occurrence of temporomandibular disorders (TMDs) and temporomandibular joint (TMJ) osteoarthritis (OA) during adolescence may have interactions with mandibular and dental development. The aim of the present study was to investigate relationships between occurrence of TMD and TMJ OA and extents of dental and skeletal development in juvenile female patients. In total, 95 female adolescents (age range, 11-15 years) were selected. Among them, 15 subjects (control) had no signs of TMD, 39 TMD patients did not have OA (TMDnoOA), 17 TMD patients were at initial stage of TMJ OA (TMJOA), and 27 patients showed progressive stage of TMJ OA (TMJOA). Dental age was estimated by Demirjian's stages used in a previous study with Korean adolescents. Craniofacial parameters and cervical vertebrae maturation (CVM) stages, representing skeletal maturity levels, were measured using lateral cephalograms. The estimated dental age was significantly lower than chronological age in all groups, but CVM differences were not statistically significant. Dental age was the lowest, and differences between the chronological age and estimated dental age were the highest among initial stage of TMJOAs followed by progressive stage of TMJOAs, TMDnoOAs and control and were not associated with CVM stages. Cephalometric parameters revealed significant clockwise rotation of the mandible among the TMJOAs compared with controls and TMDnoOAs and were not associated with CVM stages as well. The juvenile female patients with TMD, particularly TMJ OA, showed retarded dental development, mandibular backward positioning and hyperdivergent facial profiles. The TMJ OA may be associated with retarded dental development but not with skeletal maturations., (© 2017 John Wiley & Sons Ltd.)