Radiographic evaluation of the forelimb bone development in maned wolves (Chrysocyon brachyurus).

This study aimed to assess the fusion of growth plates and the development of secondary ossification centres in the forelimb bones of maned wolves (Chrysocyon brachyurus), contrasting the findings with established data from domestic dogs. Three maned wolves, comprising one male and two females, initially aged between 3 and 4 months, were subjected to monthly radiographic evaluations until 10-11 months of age, followed by bimonthly assessments until 18-19 months of age, encompassing both forelimbs. The closure times of growth plates were observed as follows: supraglenoid tubercle (7-8 months), proximal humerus (17-19 months), distal humerus (8-9 months), medial epicondyle of the humerus (8-9 months), proximal ulna (9-10 months), proximal radius (13-15 months), distal ulna (13-15 months) and distal radius (17-19 months). Statistical analysis revealed significant differences in the areas of secondary ossification centres in the proximal epiphyses of the humerus and radius, respectively, observed from the initial evaluation at 8-9 months and 6-7 months. Conversely, the epiphyses of the supraglenoid tubercle, distal humerus, proximal ulna, distal ulna, medial epicondyle of the humerus and distal radius did not exhibit significant area differences between 3-4 months and 4-5 months, yet notable distinctions emerged at 5-6 months. In summary, while the radiographic appearance of epiphyseal growth plates and secondary ossification centres in maned wolves resembles that of domestic dogs, closure times vary. These findings contribute to understanding the dynamics of epiphyseal growth plates in this species.

Impact of dairy supplementation on bone acquisition in children's limbs: a 12-month cluster-randomized controlled trial and meta-analysis.

The impact of milk on bone health in rural preschoolers is under-researched. This study, through a clinical trial and a meta-analysis, finds that milk supplementation enhances forearm and calcaneus bone acquisition in children, supporting the benefits of daily milk consumption. PURPOSE: This study evaluated the impact of dairy supplementation on bone acquisition in children's limbs through a cluster-randomized controlled trial and a meta-analysis. METHODS: The trial involved 315 children (4-6 year) from Northwest China, randomized to receive either 390 ml of milk daily (n = 215) or 20-30 g of bread (n = 100) over 12 months. We primarily assessed bone mineral density (BMD) and content (BMC) changes at the limbs, alongside bone-related biomarkers, measured at baseline, the 6th and 12th months. The meta-analysis aggregated BMD or BMC changes in the forearm/legs/calcaneus from published randomized trials involving children aged 3-18 years supplemented with dairy foods (vs. control group). RESULTS: Of 278 completed the trial, intention-to-treat analysis revealed significant increases in BMD (4.05% and 7.31%) and BMC (4.69% and 7.34%) in the left forearm at the 6th and 12th months in the milk group compared to controls (P < 0.001). The calcaneus showed notable improvements in BMD (2.01%) and BMC (1.87%) at 6 months but not at 12 months. Additionally, milk supplementation was associated with beneficial changes in bone resorption markers, parathyroid hormone (- 12.70%), insulin-like growth factor 1 (6.69%), and the calcium-to-phosphorus ratio (2.22%) (all P < 0.05). The meta-analysis, encompassing 894 children, indicated that dairy supplementation significantly increased BMD (SMD, 0.629; 95%CI: 0.275, 0.983) and BMC (SMD, 0.616; 95%CI: 0.380, 0.851) (P < 0.05) in the arms, but not in the legs (P > 0.05). CONCLUSION: Milk supplementation significantly improves bone health in children's forearms, underscoring its potential as a strategic dietary intervention for bone development. Trial registration NCT05074836.

The Immature Pediatric Appendicular Skeleton.

Growth and maturation occur in a predictable pattern throughout the body and within each individual bone. In the appendicular skeleton, endochondral ossification predominates in long bones and growth plates. The ends of these long bones are sites of relative weakness in the immature skeleton and prone to injury from acute insult and overuse. We present the normal histoanatomy and physiology of the growth plate complex, highlighting the unique contribution of each component and shared similarities between primary and secondary complexes. Components of the growth plate complex include the physis proper, subjacent vascularity within the growth cartilage, and the ossification front. The second section describes imaging considerations and features of normal and abnormal growth. Finally, we review the Salter-Harris classification for acute fractures and offer examples of characteristic overuse injury patterns involving the epiphyseal (proximal humerus and distal radius), apophyseal (medial epicondyle and tibial tubercle), and secondary growth plate complexes (medial femoral condyle and capitellar osteochondritis dissecans). This article provides a foundation and basic framework to better understand and anticipate potential complications and growth disturbances and to ensure optimal follow-up and early intervention when treatment can be less invasive.

Transrectal ultrasonographic assessment of the fetal proximal phalanx: A new tool to assess fetal age and bone development in horses.

Fetal age in Quarter Horses can be predicted within 2 weeks from 100- to 200- days of gestation using femur length, biparietal diameter (cranium diameter) and eye approximated volume. However, as pregnancy advances, the femur and cranium become too large to be imaged in their entirety using ultrasound and the corresponding biometric parameters can no longer be measured. In this longitudinal study, the proximal phalanx (P1) was evaluated as a novel biometric parameter for late gestation to predict fetal age and bone maturation. Transrectal ultrasound was performed in ten pregnant mares with known ovulation dates, every two weeks from 240- days of gestation until parturition. P1 was imaged in 69 % of the examinations. Inability to image P1 was due to obstructive positioning such as carpal or fetlock flexion, or posterior presentation of the fetus. Advancing fetal age did not affect visibility of P1. P1 length correlated significantly with days of gestation and a correlation equation was established: y = 0.3837x -69.55 where y is the predicted value of P1 length and x is the day of gestation (with day 0 being the day of ovulation). When P1 length was equal to or larger than the width of the ultrasound image (52.5 mm), 90 % of mares (9/10) were above 300- days of gestation. Ossification of the proximal and distal epiphysis of P1 typically appeared between 277- and 303 -days of gestation (mean: 288 days). The proximal epiphysis did not close before parturition whereas the distal one closed between 306- and 333-days of gestation (mean: 320 days). P1 epiphyseal appearance and closure occurred chronologically reflecting bone maturation. Radiographic findings at birth and prenatal ultrasound findings were in agreement, apart from timing of P1 distal epiphyseal closure. In conclusion, P1 length can be used as a new fetal biometric parameter to assess fetal age and growth after 240- days of gestation. The knowledge of P1 bone maturation process in utero as a marker for fetal bone development, may also be valuable in clinical decision-making when considering inducing parturition in the mare.

Central obesity may affect bone development in adolescents: association between abdominal obesity index ABSI and adolescent bone mineral density.

PURPOSE: Previous studies have suggested that obesity defined by body mass index(BMI) is a protective factor for bone mineral density(BMD), but have overlooked the potential influence of different types of obesity. This study aims to evaluate the correlation between abdominal obesity index A Body Shape Index(ABSI) and adolescent bone density, and analyze the relationship between abdominal obesity and bone metabolism. METHODS: A total of 1557 adolescent participants were included in NHANES from 2007 to 2018. Calculate the ABSI using a specific formula that takes into account waist circumference and BMI. A weighted multiple linear regression model is used to evaluate the linear correlation between ABSI and BMD. Forest plots are used to analyze the correlations between subgroups, and cubic splines are limited to evaluate the nonlinear correlations and saturation effects between ABSI and BMD. RESULTS: After adjusting for confounding factors, there was a significant linear correlation (P < 0.01) between ABSI and femoral BMD, both as a continuous variable and an ordered categorical variable. The restrictive cubic spline curve indicates a significant nonlinear correlation and saturation effect between adolescent ABSI and BMD. CONCLUSION: Research has shown a significant negative correlation between ABSI and BMD at the four detection sites of the femur, and this correlation may vary slightly due to age, race, family income, and different detection sites. The research results indicate that compared to overall body weight, fat distribution and content may be more closely related to bone metabolism.

Cohort profile of an early life observational cohort in China: Bone and MicroBiOme onset (BAMBOO) study.

PURPOSE: The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate trajectories for microbiome maturation and bone development and to identify the influence of dietary factors in the process. PARTICIPANTS: The recruitment started in September 2021 and was completed in February 2023. A total of 1380 subjects were recruited, 690 at birth (group 1) and 690 at 6 months of age (group 2). Groups 1 and 2 will be followed up for 12 months and 36 months, respectively. FINDINGS TO DATE: The age of the mothers was 31.1±3.7 (mean±SD), and the birth weight of infants was 3.3±0.5 kg with an incidence of caesarean section 50.4%. Food diary information of the first 100 subjects showed that 64 food items were introduced by 6 months. A pilot microbiome analysis revealed that at the species level, bacterial communities were composed of mostly Bacteroides dorei, Bacteroides vulgatus and Escherichia coli, which were consistent with that of previous reports. Feasibility assessments of breast milk vitamin D and human milk oligosaccharides were validated through certified reference measurements. The early data assessment showed a high reliability of the data generated from this study. FUTURE PLANS: Data collection will be completed in August 2025. Four stage-statistical analyses will be performed as the cohort reaches certain age thresholds before the final report. Analysis of BAMBOO data will be used to develop age-appropriate trajectories for microbiome maturation and bone development for children aged 0-3 years and investigate the contribution of dietary factors in the process. TRIAL REGISTRATION NUMBER: ChiCTR2100049972.

Hormonal Control of Bone Architecture Throughout the Lifespan: Implications for Fracture Prediction and Prevention.

BACKGROUND: Skeletal modeling in childhood and adolescence and continuous remodeling throughout the lifespan are designed to adapt to a changing environment and resist external forces and fractures. The flux of sex steroids in men and women, beginning from fetal development and evolving through infancy, childhood, puberty, young adulthood, peri/menopause transition, and postmenopause, is critical for bone size, peak bone mass, and fracture resistance. OBJECTIVE: This review will highlight how changes in sex steroids throughout the lifespan affect bone cells and the consequence of these changes on bone architecture and strength. METHODS: Literature review and discussion. RESULTS: The contributions of estrogen and testosterone on skeletal development have been difficult to study due to the reciprocal and intertwining contributions of one on the other. Although orchiectomy in men renders circulating testosterone absent, circulating estrogen also declines due to testosterone being the substrate for estradiol. The discovery of men with absent estradiol or resistance to estrogen and the study of mouse models led to the understanding that estrogen has a larger direct role in skeletal development and maintenance in men and women. The mechanistic reason for larger bone size in men is incompletely understood but related to indirect effects of testosterone on the skeleton, such as higher muscle mass leading to larger mechanical loading. Declines in sex steroids during menopause in women and androgen deprivation therapies in men have profound and negative effects on the skeleton. Therapies to prevent such bone loss are available, but how such therapies can be tailored based on bone size and architecture remains an area of investigation. CONCLUSION: In this review, the elegant interplay and contribution of sex steroids on bone architecture in men and women throughout the lifespan is described.

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Runt-related transcription factor (RUNX1) is a transcription factor closely involved in hematopoiesis. RUNX1 gene mutation plays an essential pathogenic role in the initiation and development of hematological tumors, especially in acute myeloid leukemia. Recent studies have shown that RUNX1 is also involved in the regulation of bone development and the pathological progression of bone-related diseases. RUNX1 promotes the differentiation of mesenchymal stem cells into chondrocytes and osteoblasts and modulates the maturation and extracellular matrix formation of chondrocytes. The expression of RUNX1 in mesenchymal stem cells, chondrocytes, and osteoblasts is of great significance for maintaining normal bone development and the mass and quality of bones. RUNX1 also inhibits the differentiation and bone resorptive activities of osteoclasts, which may be influenced by sexual dimorphism. In addition, RUNX1 deficiency contributes to the pathogenesis of osteoarthritis, delayed fracture healing, and osteoporosis, which was revealed by the RUNX1 conditional knockout modeling in mice. However, the roles of RUNX1 in regulating the hypertrophic differentiation of chondrocytes, the sexual dimorphism of activities of osteoclasts, as well as bone loss in diabetes mellitus, senescence, infection, chronic inflammation, etc, are still not fully understood. This review provides a systematic summary of the research progress concerning RUNX1 in the field of bone biology, offering new ideas for using RUNX1 as a potential target for bone related diseases, especially osteoarthritis, delayed fracture healing, and osteoporosis.

Noncoding RNAs in skeletal development and disorders.

Protein-encoding genes only constitute less than 2% of total human genomic sequences, and 98% of genetic information was previously referred to as "junk DNA". Meanwhile, non-coding RNAs (ncRNAs) consist of approximately 60% of the transcriptional output of human cells. Thousands of ncRNAs have been identified in recent decades, and their essential roles in the regulation of gene expression in diverse cellular pathways associated with fundamental cell processes, including proliferation, differentiation, apoptosis, and metabolism, have been extensively investigated. Furthermore, the gene regulation networks they form modulate gene expression in normal development and under pathological conditions. In this review, we integrate current information about the classification, biogenesis, and function of ncRNAs and how these ncRNAs support skeletal development through their regulation of critical genes and signaling pathways in vivo. We also summarize the updated knowledge of ncRNAs involved in common skeletal diseases and disorders, including but not limited to osteoporosis, osteoarthritis, rheumatoid arthritis, scoliosis, and intervertebral disc degeneration, by highlighting their roles established from in vivo, in vitro, and ex vivo studies.

Resistance training presents beneficial effects on bone development of adolescents engaged in swimming but not in impact sports: ABCD Growth Study.

BACKGROUND: Sports practice during adolescence is important to enhance bone development, although it may provide different effects depending on the mechanical impact present in the sport. Besides, resistance training (RT) may also induce bone changes directly (via muscle contractions) and indirectly (via myokines). However, there have been no studies analyzing the longitudinal influence of engaging in sport with and without added mechanical load. Thus, this study aims to analyze the combined effects of sports participation and resistance training on areal bone mineral density (aBMD) accrual in adolescent athletes participating in swimming and impact sports for 12-months. METHODS: This was a 12-month longitudinal study. The sample comprised 91 adolescents (21 females) aged 10 to 18 years, engaged in impact sports (basketball, tennis, track & field, baseball and gymnastics, n = 66) and non-impact sport (swimming, n = 25). The sample was divided according to resistance training participation: impact sports only (n = 45), impact sports + resistance training (n = 21), swimming-only (n = 17) and swimming + resistance training (n = 8). aBMD and soft tissues were measured using dual-energy X-ray absorptiometry. Generalized linear models analysis was used for the resistance training (RT) x type of sport interaction in predicting aBMD changes overtime, adjusting for maturation, sex and baseline aBMD. RESULTS: After 12-months, all groups showed a significant increase in aBMD, except for the swimming groups (regardless of resistant training), which showed a significant loss in spine aBMD (-0.045 [-0.085 to -0.004] g/cm2 in swimming-only and - 0.047 [-0.073 to -0.021] g/cm2 in swimming + RT). In comparisons between groups, only swimming + RT group, compared with swimming-only group presented higher upper limbs aBMD (0.096 g/cm2 [0.074 to 0.118] in swimming + RT vs. 0.046 [0.032 to 0.060] g/cm2 in swimming only; p < 0.05) and whole body less head (WBLH) aBMD (0.039 [0.024 to 0.054] g/cm2 in swimming + RT vs. 0.017 [0.007 to 0.027] g/cm2 swimming-only; p < 0.05). CONCLUSION: Despite the significant gain in aBMD in all groups and body sites after 12-months, except for the spine site of swimmers, the results indicate that participation in RT seems to improve aBMD accrual in swimmers at the upper limbs and WBLH.

Metabolic regulation of skeletal cell fate and function.

Bone development and bone remodelling during adult life are highly anabolic processes requiring an adequate supply of oxygen and nutrients. Bone-forming osteoblasts and bone-resorbing osteoclasts interact closely to preserve bone mass and architecture and are often located close to blood vessels. Chondrocytes within the developing growth plate ensure that bone lengthening occurs before puberty, but these cells function in an avascular environment. With ageing, numerous bone marrow adipocytes appear, often with negative effects on bone properties. Many studies have now indicated that skeletal cells have specific metabolic profiles that correspond to the nutritional microenvironment and their stage-specific functions. These metabolic networks provide not only skeletal cells with sufficient energy, but also biosynthetic intermediates that are necessary for proliferation and extracellular matrix synthesis. Moreover, these metabolic pathways control redox homeostasis to avoid oxidative stress and safeguard cell survival. Finally, several intracellular metabolites regulate the activity of epigenetic enzymes and thus control the fate and function of skeletal cells. The metabolic profile of skeletal cells therefore not only reflects their cellular state, but can also drive cellular activity. Insight into skeletal cell metabolism will thus not only advance our understanding of skeletal development and homeostasis, but also of skeletal disorders, such as osteoarthritis, diabetic bone disease and bone malignancies.

Early history of the study of bone growth (1722-1875).

INTRODUCTION: Bone growth is a fascinating process, primarily due to its complexity. Equally engaging is the history of its study, which, however, remains unknown to most anatomists and surgeons. MATERIALS AND METHODS: A literature search was performed in original publications and historical sources. RESULTS: The early history of bone growth study may be divided into two periods. Firstly, the experimental one, between 1722 and 1847, which consisted in the study of bone growth by the drilling of benchmark holes into the diaphysis, and examination of growing bones in madder-fed animals. In the course of one century, four French scientists (Henri-Louis Duhamel du Monceau, Marie-Jean-Pierre Flourens, Gaspard Auguste Brullé and Frédéric Léopold Hugueny) and one British researcher (John Hunter) proved experimentally that the longitudinal growth of long bones occurred only at its epiphyseal ends and their final shape resulted from apposition and resorption processes taking place simultaneously both on the periosteal and intramedullary surfaces of the bone. In the second, the microscopic period (1836-1875), the physeal growth cartilage was discovered and described in detail, including its importance for the longitudinal growth of long bones. The first description of growth cartilage was published by a Swiss anatomist Miescher in 1836. Subsequently, this structure was studied by a number of English, German and French anatomists and surgeons. This whole period was concluded by Alfred Kölliker´s extensive study of bone resorption and its significance for typical bone shapes and Karl Langer´s study of the vascular supply of the growing and mature bone. CONCLUSION: Research by French, English, German and Swiss scientists between 1727 and 1875 yielded fundamental insights into the growth of long bones, most of which are still valid today.

Inter-arm bone mass and size asymmetries in children tennis players are maturity status specific: a 9-month study on the effects of training time across pubertal change and somatic growth.

PURPOSE: Bone growth with exercise is best assessed by tennis-induced inter-arm asymmetries. Yet, the effects of training and maturation across puberty were unclear. This study explored arm bone growth across 9 months of training in 46 tennis players 7-14 years (25 boys, 21 girls). METHODS: Bone mineral content (BMC) and bone area (BA) were measured from DXA scans. Pubertal status was assessed by Tanner stage (TS) and somatic growth by maturity offset (MO). Children were grouped as pre- (TS I-I), early (TS I-II), and mid/late pubertal (TS II-III). RESULTS: Training time (TT) change in the three groups was 160-170, 190-230, and 200-220 h, respectively. Bone asymmetries were large in all groups (d > 0.8, P < 0.001): 5-18 g (9-21%) and 9-17 g (17-23%) in girls and boys, respectively, for BMC, and 5-15 cm2 (6-13%) and 9-15 cm2 (12-15%) in girls and boys (10-13%), respectively, for BA. BMC and BA change asymmetry peaked at pre-puberty in girls (56%, 46%) and at early puberty in boys (57%, 43%). Asymmetry gains varied with baseline asymmetry (41%) and change in TT (38%) and TS (17%) in BMC, and with baseline asymmetry (58%) and change in MO (17%) and TS (12%) in BA. CONCLUSION: All bone asymmetries were substantial. Tennis-induced bone gains were higher at pre- to early puberty in girls and at early to mid/late puberty in boys. Training enhanced mostly bone mass and maturity status enhanced mostly bone size; sex was not bone-change modeling impactful. Implications are discussed considering certain limitations.

Chondrocyte hypertrophy in the growth plate promotes stress anisotropy affecting long bone development through chondrocyte column formation.

The length of long bones is determined by column formation of proliferative chondrocytes and subsequent chondrocyte hypertrophy in the growth plate during bone development. Despite the importance of mechanical loading in long bone development, the mechanical conditions of the cells within the growth plate, such as the stress field, remain unclear owing to the difficulty in investigating spatiotemporal changes within dynamically growing tissues. In this study, the mechanisms of longitudinal bone growth were investigated from a mechanical perspective through column formation of proliferative chondrocytes within the growth plate before secondary ossification center formation using continuum-based particle models (CbPMs). A one-factor model, which simply describes essential aspects of a biological signaling cascade regulating cell activities within the growth plate, was developed and incorporated into CbPM. Subsequently, the developmental process and maintenance of the growth plate structure and resulting bone morphogenesis were simulated. Thus, stress anisotropy in the proliferative zone that affects bone elongation through chondrocyte column formation was identified and found to be promoted by chondrocyte hypertrophy. These results provide further insights into the mechanical regulation of multicellular dynamics during bone development.

Development of a simplified new method of bone age estimation using three bones of the hand and wrist.

Though the Greulich and Pyle (GP) method is easy, inter-observer variability, differential maturation of hand bones influences ratings. The Tanner-Whitehouse (TW) method is more accurate, but cumbersome. A simpler method combining the above, such that it utilizes fewer bones without affecting accuracy, would be widely used and more applicable in clinical practice. OBJECTIVES: 1. Devising a simplified method utilizing three bones of the hand and wrist for bone age (BA) assessment. 2. Testing whether the 3 bone method gives comparable results to standard methods (GP,TW2,TW3) in Indian children. METHODS: Developmental stages and corresponding BA for radius, hamate, terminal phalanx (left middle finger) epiphyses combining stages from GP,TW3 atlases were described; BA were rated by two blinded observers. 3 bone method ratings were compared with the same dataset analyzed earlier using GP,TW2,TW3 (4 raters). RESULTS: Radiographs analysed:493 (Girls=226). Mean chronological age:9.4 ± 4.6 yrs, mean BA 3 bone:9.8 ± 4.8 yrs, GP:9.6 ± 4.8 yrs, TW3:9.3 ± 4.5 yrs, TW2:9.9 ± 5.0 yrs. The 3 bone method demonstrated no significant inter-observer variability (p = 0.3, mean difference = 0.02 ± 0.6 yrs); a strong positive correlation (p < 0.0001) with GP (r = 0.985), TW3 (r = 0.983) and TW2 (r = 0.982) was noted. Bland-Altman plots demonstrated good agreement; the root mean square errors between 3 bone and GP,TW3,TW2 ratings were 0.6,0.7,0.6 years; mean differences were 0.19,0.49,-0.14 years respectively. Greatest proportion of outliers (beyond ±1.96 SD of mean difference) was between 6 and 8 years age for difference in 3 bone and GP, and between 4-6 years for difference in 3 bone and TW3,TW2. CONCLUSION: The 3 bone method has multiple advantages; it is easier, tackles differential maturation of wrist and hand bones, has good reproducibility, without compromising on accuracy rendering it suitable for office practice.

Gut microbiota in regulation of childhood bone growth.

Childhood stunting and wasting, or decreased linear and ponderal growth associated with undernutrition, continue to be a major global public health challenge. Although many of the current therapeutic and dietary interventions have significantly reduced childhood mortality caused by undernutrition, there remain great inefficacies in improving childhood stunting. Longitudinal bone growth in children is governed by different genetic, nutritional and other environmental factors acting systemically on the endocrine system and locally at the growth plate. Recent studies have shown that this intricate interplay between nutritional and hormonal regulation of the growth plate could involve the gut microbiota, highlighting the importance of a holistic approach in tackling childhood undernutrition. In this review, I focus on the mechanistic insights provided by these recent advances in gut microbiota research and discuss ongoing development of microbiota-based therapeutics in humans, which could be the missing link in solving undernutrition and childhood stunting.

The Origin and Fate of Chondrocytes: Cell Plasticity in Physiological Setting.

PURPOSE OF REVIEW: Here, we discuss the origin of chondrocytes, their destiny, and their plasticity in relationship to bone growth, articulation, and formation of the trabeculae. We also consider these processes from a biological, clinical, and evolutionary perspective. RECENT FINDINGS: Chondrocytes, which provide the template for the formation of most bones, are responsible for skeletal growth and articulation during postnatal life. In recent years our understanding of the fate of these cells has changed dramatically. Current evidence indicates a paradoxical situation during skeletogenesis, with some cells of mesenchymal condensation differentiating directly into osteoblasts, whereas others of the same kind give rise to highly similar osteoblasts via a complex process of differentiation involving several chondrocyte intermediates. The situation becomes even more paradoxical during postnatal growth when stem cells in the growth plate produce differentiated, functional progenies, which thereafter presumably dedifferentiate into another type of stem cell. Such a remarkable transition from one cell type to another under postnatal physiological conditions provides a fascinating example of cellular plasticity that may have valuable clinical implications.

Impact loading intensifies cortical bone (re)modeling and alters longitudinal bone growth of pubertal rats.

Physical exercise is important for musculoskeletal development during puberty, which builds bone mass foundation for later in life. However, strenuous levels of training might bring adverse effects to bone health, reducing longitudinal bone growth. Animal models with various levels of physical exercise were largely used to provide knowledge to clinical settings. Experiments from our previous studies applied different levels of mechanical loading on rat tibia during puberty accompanied by weekly in vivo micro-CT scans. In the present article, we apply 3D image registration-based methods to retrospectively analyze part of the previously acquired micro-CT data. Longitudinal bone growth, growth plate thickness, and cortical bone (re)modeling were evaluated from rats' age of 28-77 days. Our results show that impact loading inhibited proximal bone growth throughout puberty. We hypothesize that impact loading might bring different growth alterations to the distal and proximal growth plates. High impact loading might lead to pathological consequence of osteochondrosis and catch-up growth due to growth inhibition. Impact loading also increased cortical bone (re)modeling before and after the peak proximal bone growth period of young rats, of which the latter case might be caused by the shift from modeling to remodeling as the dominant activity toward the end of rat puberty. We confirm that the tibial endosteum is more mechano-sensitive than the periosteum in response to mechanical loading. To our knowledge, this is the first study to follow up bone growth and bone (re)modeling of young rats throughout the entire puberty with a weekly time interval.

An in silico model for woven bone adaptation to heavy loading conditions in murine tibia.

Existing in silico models for lamellar bone adaptation to mechanical loading are unsuitable for predicting woven bone growth. This anomaly is due to the difference in mechanobiology of the woven bone with respect to that of the lamellar bone. The present study is aimed at developing an in silico bone-adaptation model for woven bone at cellular and tissue levels. The diffusion of Ca2+ ions reaching lining cells from the osteocytic network and the bone cortex in response to a mechanical loading on the cortical bone has been considered as a stimulus. The diffusion of ions within osteocytic network has been computed with a lacunar-canalicular network (LCN) in which bone cells are uniformly arranged. Strain energy density is assumed to regulate ion flow within the network when the induced normal strain is above a threshold level. If the induced strain exceeds another higher threshold level, then the strain with a power constant is additionally assumed to regulate the stimulus. The intracellular flow of Ca2+ ions within the LCN has been simulated using Fick's laws of diffusion, using a finite element method. The ion diffusion from bone cortex to vesicles has been formulated as a normal strain with a power constant. The stimuli reaching the surface cells are assumed to form the new bone. The mathematical model closely predicts woven bone growth in mouse and rat tibia for various in vivo loading conditions. This model is the first to predict woven bone growth at tissue and cellular levels in response to heavy mechanical loading.

Nox4 expression in osteo-progenitors controls bone development in mice during early life.

Tightly regulated and cell-specific NADPH-oxidases (Nox) represent one of the major sources of reactive oxygen species (ROS) signaling molecules that are involved in tissue development and stem cell self-renewal. We have characterized the role of Nox4 in osteo-progenitors during postnatal bone development. Nox4 expression in bone and ROS generation were increased during early osteoblast differentiation and bone development. Stromal osteoblastic cell self-renewal, proliferation and ROS production were significantly lower in samples from whole-body Nox4 knockout mice (Nox4-/-) and conditional knockout (CKO) mice with depletion of Nox4 in the limb bud mesenchyme compared with those from control mice (Nox4fl/fl), but they were reversed after 9 passages. In both sexes, bone volume, trabecular number and bone mineral density were significantly lower in 3-week old CKO and Nox4-/- mice compared with Nox4fl/fl controls. This was reflected in serum levels of bone formation markers alkaline phosphatase (ALP) and procollagen 1 intact N-terminal propeptide (P1NP). However, under-developed bone formation in 3-week old CKO and Nox4-/- mice quickly caught up to levels of control mice by 6-week of age, remained no different at 13-week of age, and was reversed in 32-week old male mice. Osteoclastogenesis showed no differences among groups, however, CTX1 reflecting osteoclast activity was significantly higher in 3-week old male CKO and Nox4-/- mice compared with control mice, and significantly lower in 32-week old Nox4-/- mice compared with control mice. These data suggest that Nox4 expression and ROS signaling in bone and osteoblastic cells coordinately play an important role in osteoblast differentiation, proliferation and maturation.