Normal Bone Growth Research Articles

Retinoid-impregnated nanoparticles enable control of bone growth by site-specific modulation of endochondral ossification in mice.

Growth-plates (physes), which are cartilage tissues near the ends of bones, support normal bone growth in children. Growth plate injures in limbs and other sites can impair growth plate function, leading to inhibited or imbalanced bone growth, skeletal deformities, decreased motion, discomfort or pain. At present, surgical interventions are the only means available to correct these conditions. Here, we aimed to develop a pharmacologic treatment for bone growth imbalance. Nanoparticles loaded with a selective agonist for the retinoic acid nuclear receptor gamma were prepared and implanted near the tibial growth plate in juvenile mice. The growth plate underwent involution and closure, and overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the same drug nanoparticles were implanted in only one side of the tibia, the tibia was tilted toward the injection site. Our findings provide novel evidence that retinoic acid receptor gamma agonist-loaded nanoparticles can control activity, function and directionality of a targeted growth plate, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length imbalances and deformities.

Osteosarcoma through the Lens of Bone Development, Signaling, and Microenvironment.

In this work, we review the multifaceted connections between osteosarcoma (OS) biology and normal bone development. We summarize and critically analyze existing research, highlighting key areas that merit further exploration. The review addresses several topics in OS biology and their interplay with normal bone development processes, including OS cell of origin, genomics, tumor microenvironment, and metastasis. We examine the potential cellular origins of OS and how their roles in normal bone growth may contribute to OS pathogenesis. We survey the genomic landscape of OS, highlighting the developmental roles of genes frequently altered in OS. We then discuss the OS microenvironment, emphasizing the transformation of the bone niche in OS to facilitate tumor growth and metastasis. The role of stromal and immune cells is examined, including their impact on tumor progression and therapeutic response. We further provide insights into potential development-informed opportunities for novel therapeutic strategies.

Relative contributions of osteal macrophages and osteoclasts to postnatal bone development in CSF1R-deficient rats and phenotype rescue following wild-type bone marrow cell transfer.

Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor-1 receptor (CSF1R) signaling. Osteopetrosis associated with Csf1 and Csf1r mutations has been attributed to the loss of osteoclasts and deficiency in bone resorption. Here we demonstrate that homozygous Csf1r mutation in rat leads to delayed postnatal skeletal ossification associated with substantial loss of osteal macrophages (osteomacs) in addition to osteoclasts. Osteosclerosis and site-specific skeletal abnormalities were reversed by intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning. Following BMT, IBA1+ macrophages were detected before TRAP+ osteoclasts at sites of ossification restoration. These observations extend evidence that osteomacs independently contribute to bone anabolism and are required for normal postnatal bone growth and morphogenesis.

Evidence of non-adult vitamin C deficiency in three early medieval sites in the Jaun/Podjuna Valley, Carinthia, Austria

ObjectiveThis study aims to determine and discuss the prevalence of non-adult scurvy cases from the early medieval Jaun/Podjuna Valley in southern Austria. Materials86 non-adult individuals were assessed from three early medieval sites. MethodsMorphological characteristics associated with suggestive and probable scurvy were observed macroscopically and under 20–40x magnification. ResultsA significant relationship between the prevalence of scurvy and age group was observed. Perinates (46%, 6/13) and children (27.5%, 8/28) showed a high prevalence of skeletal features indicating a diagnosis of scurvy, while no cases of scurvy were observed in adolescents and adults. ConclusionsIn this Alpine region, scurvy occurred frequently in infants and children. Seasonal fluctuations of diet are discussed as factors triggering scurvy. SignificanceThis study sheds new light on the prevalence of scurvy in the Alpine region and how the region developed after the fall of the Roman Noricum. It also models ways in which multiple lines of evidence can contribute to the diagnostic process. LimitationsPoor preservation posed a challenge to identifying probable cases of scurvy. Likewise, non-adult remains are difficult to diagnose due to their developing nature and it is not always possible to distinguish between normal bone growth and pathological growth. Suggestions for further researchFuture applications of biomolecular studies will help illustrate changes in diet that may have contributed to vitamin deficiencies.

FBXO11 regulates bone development.

FBXO11 is the substrate-recognition component of a ubiquitin ligase complex called SKP1-cullin-F-boxes. The role of FBXO11 in bone development is unexplored. In this study, we reported a novel mechanism of how bone development is regulated by FBXO11. FBXO11 gene knockdown by lentiviral transduction in mouse pre-osteoblast MC3T3-E1 cells leads to reduced osteogenic differentiation, while overexpressing FBXO11 accelerates their osteogenic differentiation in vitro. Furthermore, we generated two osteoblastic-specific FBXO11 conditional knockout mouse models, Col1a1-ERT2-FBXO11KO and Bglap2-FBXO11KO mice. In both conditional FBXO11KO mouse models, we found FBXO11 deficiency inhibits normal bone growth, in which the osteogenic activity in FBXO11cKO mice is reduced, while osteoclastic activity is not significantly changed. Mechanistically, we found FBXO11 deficiency leads to Snail1 protein accumulation in osteoblasts, leading to suppression of osteogenic activity and inhibition of bone matrix mineralization. FBXO11 knockdown in MC3T3-E1 cells reduced Snail1 protein ubiquitination and increased Snail1 protein accumulation in the cells, which eventually inhibited osteogenic differentiation. In conclusion, FBXO11 deficiency in osteoblasts inhibits bone formation through Snail1 accumulation, inhibiting osteogenic activity and bone mineralization.

Histological Assessment of Endochondral Ossification and Bone Mineralization

Finely tuned cartilage mineralization, endochondral ossification, and normal bone formation are necessary for normal bone growth. Hypertrophic chondrocytes in the epiphyseal cartilage secrete matrix vesicles, which are small extracellular vesicles initiating mineralization, into the intercolumnar septa but not the transverse partitions of the cartilage columns. Bone-specific blood vessels invade the unmineralized transverse septum, exposing the mineralized cartilage cores. Many osteoblast precursors migrate to the cartilage cores, where they synthesize abundant bone matrices, and mineralize them in a process of matrix vesicle-mediated bone mineralization. Matrix vesicle-mediated mineralization concentrates calcium (Ca) and inorganic phosphates (Pi), which are converted into hydroxyapatite crystals. These crystals grow radially and are eventually get out of the vesicles to form spherical mineralized nodules, leading to collagen mineralization. The influx of Ca and Pi into the matrix vesicle is regulated by several enzymes and transporters such as TNAP, ENPP1, PiT1, PHOSPHO1, annexins, and others. Such matrix vesicle-mediated mineralization is regulated by osteoblastic activities, synchronizing the synthesis of organic bone material. However, osteocytes reportedly regulate peripheral mineralization, e.g., osteocytic osteolysis. The interplay between cartilage mineralization and vascular invasion during endochondral ossification, as well as that of osteoblasts and osteocytes for normal mineralization, appears to be crucial for normal bone growth.

Severe osteoarthritis at unexpected age

Abstract Introduction Acromegaly is a rare chronic endocrine disease caused by a growth hormone (GH) – producing adenoma, resulting in elevated GH and insulin-like growth factor-1 (IGF-1) concentrations. GH and IGF-1 are essential for normal growth, differentiation, and repair of cartilage and bone; however, excess GH and IGF-1, which are characteristic of acromegaly, lead to an arthropathy that resembles osteoarthritis. Patients with acromegaly, whether it's surgically treated or biochemically controlled, still have a high risk of developing arthropathy. Clinical Case A 49-year-old woman presents to the university hospital for a visit with a complaint of knee pain. Her medical history reveals that she received an acromegaly diagnosis in 2010 and had been treated with surgery. However, she was not remission after the surgery; the patient's IGF-1 level was 686 ng/ml (Normal range: 109–284) when she presented. Her medical history reveals that she has been taking analgesics for the last four years. She has received octreotide (once-monthly 10 mg) and cabergoline (once-weekly 1 mg). The last laboratory results showed that her IGF-1 level had decreased dramatically; to 125 ng/ml. Based on the complaint of knee pain, imaging studies, including an X-ray, showed severe osteoarthritis. Conclusion Acromegalic arthropathy is one of acromegaly's most critical functional disabilities. In our case, radiographic imaging studies at joint sites show severe osteoarthritis. Considering the patient's medical history, the cause of knee pain is osteoarthritis, which is also caused by acromegaly. We should also be aware that; long-term biochemical control of acromegaly may not prevent the progression of acromegalic arthropathy in many patients. The prevalence of clinical and radiological acromegalic osteoarthritis of the hip, hand and knee reaches even up to 80%.

Juvenile toxicity study of PF-07256472/recifercept, a recombinant human soluble fibroblast growth factor receptor 3, in 2-3-month-old cynomolgus monkeys.

Achondroplasia is an autosomal disorder caused by point mutation in the gene encoding fibroblast growth factor receptor 3 (FGFR3) and resulting in gain of function. Recifercept is a potential disease modifying treatment for achondroplasia and functions as a decoy protein that competes for ligands of the mutated FGFR3. Recifercept is intended to restore normal bone growth by preventing the mutated FGFR3 from negative inhibitory signaling in pediatric patients with achondroplasia. Here we evaluated the potential effects of twice weekly administration of recifercept to juvenile cynomolgus monkeys (approximately 3-months of age at the initiation of dosing) for 6-months. No adverse effects were noted in this study, identifying the high dose as the no-observed-adverse-effect-level and supporting the use of recifercept in pediatric patients from birth. Considering that juvenile toxicity studies in nonhuman primates are not frequently conducted, and when they are conducted they typically utilize animals ≥9months of age, this study demonstrates the feasibility of executing a juvenile toxicity study in very young monkeys prior to weaning.

Abstract No. 311 Unicameral bone cyst chemical sclerosis with regenerative bone grafting

Unicameral bone cysts (UBCs) are benign bone lesions that primarily occur in pediatric populations. UBCs are often asymptomatic, but have the potential to cause pain, pathologic fractures, or disruptions in normal bone growth. There is currently no consensus on the optimal treatment method for UBCs and existing methods demonstrate highly variable recurrence rates. This study explores an image-guided approach that combines chemical sclerosis and synthetic bone grafting to treat UBCs in a minimally invasive outpatient setting.

Reversing the miRNA -5p/-3p stoichiometry reveals physiological roles and targets of miR-140 miRNAs.

The chondrocyte-specific miR-140 miRNAs are necessary for normal endochondral bone growth in mice. miR-140 deficiency causes dwarfism and craniofacial deformity. However, the physiologically important targets of miR-140 miRNAs are still unclear. The miR-140 gene (Mir140) encodes three chondrocyte-specific microRNAs, miR-140-5p, derived from the 5' strand of primary miR-140, and miR140-3p.1 and -3p.2, derived from the 3' strand of primary miR-140. miR-140-3p miRNAs are 10 times more abundant than miR-140-5p likely due to the nonpreferential loading of miR-140-5p to Argonaute proteins. To differentiate the role of miR-140-5p and -3p miRNAs in endochondral bone development, two distinct mouse models, miR140-C > T, in which the first nucleotide of miR-140-5p was altered from cytosine to uridine, and miR140-CG, where the first two nucleotides of miR-140-3p were changed to cytosine and guanine, were created. These changes are expected to alter Argonaute protein loading preference of -5p and -3p to increase -5p loading and decrease -3p loading without changing the function of miR140-5p. These models presented a mild delay in epiphyseal development with delayed chondrocyte maturation. Using RNA-sequencing analysis of the two models, direct targets of miR140-5p, including Wnt11, were identified. Disruption of the predicted miR140-5p binding site in the 3' untranslated region of Wnt11 was shown to increase Wnt11 mRNA expression and caused a modest acceleration of epiphyseal development. These results show that the relative abundance of miRNA-5p and -3p can be altered by changing the first nucleotide of miRNAs in vivo, and this method can be useful to identify physiologically important miRNA targets.

Heritability Estimates of L*a*b* Color Space Values in Winter Squash (Cucurbita spp.)

Carotenoids serve as protective antioxidants, and function in normal vision, bone growth, cell division and differentiation, and reproduction. Winter squash (Cucurbita spp.) is an excellent dietary source of carotenoids. The range of colors from yellow to red in Cucurbita species indicates that increasing carotenoid levels through plant breeding is possible. The objective of this research was to determine the heritability of flesh color in winter squash in both Cucurbita moschata Duchesne and Cucurbita pepo L. Segregating families representing F2, BC1P1 and BC1P2 populations were created in two families of C. pepo (‘Table Gold Acorn’ × PI 314806 and ‘Table King Bush’ × PI 314806) and one family of C. moschata (‘Butterbush’ × ‘Sucrine DuBerry’). Broad-sense heritabilities were calculated for the F2, BC1P1, and BC1P2 populations within each of the three families. Heritabilities ranged from 0.19 to 0.82 for L*, 0.28 to 0.97 for chroma, and 0.12 to 0.87 for hue across all families. Transgressive segregation for color space values L* was identified in the ‘Table King Bush’ × PI 314806 C. pepo population. Our results indicate that it is possible to breed for improved flesh color in Cucurbita, but the population size and number of test locations for evaluation need to be increased to provide better heritability estimates. Cucurbita species are grown throughout the world and their availability and low price makes them an important potential source of carotenoids for human nutrition and health for all ages.

Decoronation - a treatment option of an ankylosed permanent tooth in children and adolescents

Introduction. In children and growing adolescents, ankylotic resorption (i.e., progressive replacement resorption) of a permanent tooth is a serious complication. An ankylosed tooth root is continuously resorbed and replaced with bone; normal growth of alveolar bone is disturbed and infraposition of the dental crown progresses. This article aims to present decoronation as a very good treatment option for permanent incisors diagnosed with progressive replacement resorption in children and adolescents. Case outline. A 9.5-year-old boy was referred with non-vital both upper central permanent incisors due to dental trauma. In the left one, which had been re-implanted 90 minutes after avulsion, progression of clinical and radiographic pathological signs of ankylotic resorption was observed over the months. To prevent the local arrest of alveolar ridge growth and tilting of adjacent teeth, we decoronated the ankylosed tooth. For aesthetic and functional rehabilitation adhesive bonding of his dental crown was performed. Conclusion. In growing individuals with progressive replacement resorption, a dentist should be aware of decoronation as an effective treatment option with a predictable outcome.

Effects of hypoxia on bone metabolism and anemia in patients with chronic kidney disease.

BACKGROUNDAbnormal bone metabolism and renal anemia seriously affect the prognosis of patients with chronic kidney disease (CKD). Existing studies have mostly addressed the pathogenesis and treatment of bone metabolism abnormality and anemia in patients with CKD, but few have evaluated their mutual connection. Administration of exogenous erythropoietin to CKD patients with anemia used to be the mainstay of therapeutic approaches; however, with the availability of hypoxia-inducible factor (HIF) stabilizers such as roxadustat, more therapeutic choices for renal anemia are expected in the future. However, the effects posed by the hypoxic environment on both CKD complications remain incompletely understood.AIMTo summarize the relationship between renal anemia and abnormal bone metabolism, and to discuss the influence of hypoxia on bone metabolism.METHODSCNKI and PubMed searches were performed using the key words “chronic kidney disease,” “abnormal bone metabolism,” “anemia,” “hypoxia,” and “HIF” to identify relevant articles published in multiple languages and fields. Reference lists from identified articles were reviewed to extract additional pertinent articles. Then we retrieved the and Introduction and searched the results from the literature, classified the extracted information, and summarized important information. Finally, we made our own conclusions.RESULTSThere is a bidirectional relationship between renal anemia and abnormal bone metabolism. Abnormal vitamin D metabolism and hyperparathyroidism can affect bone metabolism, blood cell production, and survival rates through multiple pathways. Anemia will further attenuate the normal bone growth. The hypoxic environment regulates bone morphogenetic protein, vascular endothelial growth factor, and neuropilin-1, and affects osteoblast/osteoclast maturation and differentiation through bone metabolic changes. Hypoxia preconditioning of mesenchymal stem cells (MSCs) can enhance their paracrine effects and promote fracture healing. Concurrently, hypoxia reduces the inhibitory effect on osteocyte differentiation by inhibiting the expression of fibroblast growth factor 23. Hypoxia potentially improves bone metabolism, but it still carries potential risks. The optimal concentration and duration of hypoxia remain unclear. CONCLUSIONThere is a bidirectional relationship between renal anemia and abnormal bone metabolism. Hypoxia may improve bone metabolism but the concentration and duration of hypoxia remain unclear and need further study.

Bioactive chitosan biguanidine-based injectable hydrogels as a novel BMP-2 and VEGF carrier for osteogenesis of dental pulp stem cells

Nowadays, vascularization and mineralization of bone defects is the main bottleneck in the bone regeneration field that is needed to be overcome and developed. Here, we prepared novel in-situ formed injectable hydrogels based on chitosan biguanidine and carboxymethylcellulose loaded with vascular endothelial growth factor (VEGF) and recombinant Bone morphogenetic protein 2 (BMP-2) and studied its influence on osteoblastic differentiation of dental pulp stem cells (DPSCs). The sequential release behavior of the VEGF and BMP-2 from hydrogels adjusted with the pattern of normal human bone growth. MTT assay exhibited that these hydrogels were non-toxic and significantly increased DPSCs proliferation. The Real-time PCR and Western blot analysis on CG11/BMP2-VEGF showed significantly higher gene and protein expression of ALP, COL1α1, and OCN. These results were confirmed by mineralization assay by Alizarin Red staining and Alkaline phosphatase enzyme activity. Based on these evaluations, these hydrogel holds potential as an injectable bone tissue engineering platform.

GnRHa/Stanozolol Combined Therapy Maintains Normal Bone Growth in Central Precocious Puberty.

BackgroundGonadotropin-releasing hormone agonist (GnRHa) is the gold standard in the treatment of Central Precocious Puberty (CPP) with progressive puberty and accelerative growth. However, GnRHa treatment is reported to result in growth deceleration and prevents growth plate development which leads to a reduction in height velocity. Stanozolol (ST) has been used to stimulate growth in patients with delayed growth and puberty, nevertheless, the effects and mechanisms of ST on CPP with GnRHa treatment are currently unclear.Methods and ResultsIn the current study, we recorded the following vital observations that provided insights into ST induced chondrogenic differentiation and the maintenance of normal growth plate development: (1) ST efficiently prevented growth deceleration and maintained normal growth plate development in rats undergoing GnRHa treatment; (2) ST suppressed the inhibitory effect of GnRHa to promote chondrogenic differentiation; (3) ST induced chondrogenic differentiation through the activation of the JNK/c-Jun/Sox9 signaling pathway; (4) ST promoted chondrogenic differentiation and growth plate development through the JNK/Sox9 signaling pathway in vivo.ConclusionsST mitigated the inhibitory effects of GnRHa and promoted growth plate development in rats. ST induced the differentiation of chondrocytes and maintained normal growth plate development through the activation of JNK/c-Jun/Sox9 signaling. These novel findings indicated that ST could be a potential agent for maintaining normal bone growth in cases of CPP undergoing GnRHa treatment.

Anesthetic management of craniosynostosis repair in a 13-month-old boy with Apert syndrome

Apert syndrome is a congenital disorder characterized by malformations of the skull, face, hands, and feet. It is a form of acrocephalosyndactyly. It is classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the precursor of the maxilla and mandible. Presently described is a case of 13-month-old boy diagnosed with apert syndrome. French pediatrician Eugène Apert described Apert syndrome in 1906. The purpose of this report is anesthetic management of craniosynostosis repair in this child under general anesthesia. Craniosynostosis, the premature fusion of skull sutures, results in failure of normal bone growth perpendicular to the suture and the compensatory growth at other suture sites, which results in an abnormally shaped head. Anesthetic challenges include management of a difficult airway, airway hyperreactivity, possibility of raised intracranial pressure, blood loss, blood transfusion, and its associated complications.

Micro-CT data of early physiological cancellous bone formation in the lumbar spine of female C57BL/6 mice

Micro-CT provides critical data for musculoskeletal research, yielding three-dimensional datasets containing distributions of mineral density. Using high-resolution scans, we quantified changes in the fine architecture of bone in the spine of young mice. This data is made available as a reference to physiological cancellous bone growth. The scans (n = 19) depict the extensive structural changes typical for female C57BL/6 mice pups, aged 1-, 3-, 7-, 10- and 14-days post-partum, as they attain the mature geometry. We reveal the micro-morphology down to individual trabeculae in the spine that follow phases of mineral-tissue rearrangement in the growing lumbar vertebra on a micrometer length scale. Phantom data is provided to facilitate mineral density calibration. Conventional histomorphometry matched with our micro-CT data on selected samples confirms the validity and accuracy of our 3D scans. The data may thus serve as a reference for modeling normal bone growth and can be used to benchmark other experiments assessing the effects of biomaterials, tissue growth, healing, and regeneration.

Monostotic fibrous dysplasia of fibula: a rare case report

<p>Fibrous dysplasia is a developmental anomaly of bone formation that may exist in monostotic or polyostotic form. Monostotic fibrous dysplasia of fibula is a rare case with unusual site and most common sites being facial bones, ribs, proximal femur and tibia. We report a case of 10-year-old boy attended our hospital with occasional pain in left leg while having strenuous activity. On clinical examination there was no obvious swelling with normal appearing skin. Radiographic examination revealed lesion with both radiopaque and radiolucent features showing a “ground-glass” appearing lesion in proximal one third of fibula. Differential diagnosis considered are simple bone cyst, non-ossifying fibroma, osteo-fibrous dysplasia, adamantinoma. As a definitive treatment curettage was done and biopsy sent for histopathological examination, which confirmed he diagnosis. Follow up after 10 months shows normal bone growth as evidenced radiologically and patient is asymptomatic. Case in detail and recent review of literature has been discussed. From our case, we have shown that it is possible to treat uncomplicated fibrous dysplasia with minimally invasive approach of simple curettage. Patient is symptomatically relieved within 2 months without any complications.</p>

New Advances in Osteocyte Mechanotransduction.

Skeletal adaptation to mechanical loading plays a critical role in bone growth and the maintenance of bone homeostasis. Osteocytes are postulated to serve as a hub orchestrating bone remodeling. The recent findings on the molecular mechanisms by which osteocytes sense mechanical loads and the downstream bone-forming factors are reviewed. Calcium channels have been implicated in mechanotransduction in bone cells for a long time. Efforts have been made to identify a specific calcium channel mediating the skeletal response to mechanical loads. Recent studies have revealed that Piezo1, a mechanosensitive ion channel, is critical for normal bone growth and is essential for the skeletal response to mechanical loading. Identification of mechanosensors and their downstream effectors in mechanosensing bone cells is essential for new strategies to modulate regenerative responses and develop therapies to treat the bone loss related to disuse or advanced age.

Progress on signal pathways related to bone metabolism in animals

Bone is a hard organ that makes up vertebrate endoskeleton, which plays a role in movement, support and protection for the body. The normal growth and development of bone is in the dynamic balance of bone metabolism, which is composed of bone formation and bone absorption. This balance is very important for maintaining bone mass and mineral homeostasis. In the process of bone growth and metabolism, there are many signaling pathways regulating bone formation and absorption, such as BMP (bone morphogenetic protein)/SMADs, TGF-β (transforming growth factor β), Wnt/β-catenin, OPG (osteoprotegerin)/RANKL (receptor activator of NF-κB ligand)/RANK (receptor activator of NF-κB), FGF (fibroblast growth factor) and Notch signaling pathway. These signaling pathways have complex regulatory mechanisms and are involved in the regulation of bone metabolism. In this review, we summarize the mechanism and research progress of signal pathways that play key regulatory roles in the process of animal bone metabolism, thereby laying a foundation for research in animal bone metabolism.