DEVELOPMENTAL SCENARIOS OF THE EPIPHYSIS AND GROWTH PLATE UPON MECHANICAL LOADING: A COMPUTATIONAL MODEL

2016 ◽  
Vol 16 (07) ◽  
pp. 1650098
Author(s):  
JOHANA MARIA GUEVARA ◽  
MARIA LUCIA GUTIERREZ GOMEZ ◽  
LUIS ALEJANDRO BARRERA LA ◽  
DIEGO ALEXANDER GARZÓN-ALVARADO
Keyword(s):  
Growth Plate ◽  
Computational Models ◽  
Bone Growth ◽  
Bone Development ◽  
Human Growth ◽  
Relevant Information ◽  
Biological Behavior ◽  
Long Bone ◽  
Mechanical Stimuli

Long bone growth relies on the continuous bone formation from cartilaginous tissue (endochondral ossification). This process starts in the central region (diaphysis) of the forming bone and short before birth, ossification starts in bone extremes (epiphysis). A cartilaginous region known as the growth plate is maintained until adolescence between epiphysis and diaphysis to further contribute to longitudinal growth. Even though there are several biochemical factors controlling this process, there is evidence revealing an important regulatory role of mechanical stimuli. Up to now approaches to understand mechanical effects on ossification have been limited to epiphysis. In this work, based on Carter's mathematical model for epiphyseal ossification, we explored human growth plate response to mechanical loads. We analyzed growth plate stress distribution using finite element method for a generic bone considering different stages of bone development in order to shed light on mechanical contribution to growth plate function. Results obtained revealed that mechanical environment within the growth plate change as epiphyseal ossification progresses. Furthermore, results were compared with physiological behavior, as reported in literature, to analyze the role of mechanical stimulus over development. Our results suggest that mechanical stimuli may play different regulation roles on growth plate behavior through normal long bone development. However, as this approach only took into account mechanical aspects, failed to accurately predict biological behavior in some stages. In order to derive biologically relevant information from computational models it is necessary to consider biological contribution and possible mechanical–biochemical interactions affecting human growth plate physiology. Along these lines, we propose the dilatatorial parameter k used by Carter et al. should assume different values corresponding to the developmental stage in question. Thus, reflecting biochemical contribution changes over time.

scholarly journals Rac signaling in osteoblastic cells is required for normal bone development but is dispensable for hematopoietic development

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 736-744 ◽  
Author(s):  
Steven W. Lane ◽  
Serena De Vita ◽  
Kylie A. Alexander ◽  
Ruchan Karaman ◽  
Michael D. Milsom ◽  
...  
Keyword(s):  
Bone Growth ◽  
Bone Development ◽  
Long Bone ◽  
Perivascular Niche ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Rac1 Gtpase

Abstract Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrate that Rac depletion causes impaired proliferation and induction of apoptosis in the OP9 cell line and in primary BM stromal cells. Deletion of Rac proteins caused reduced trabecular and cortical long bone growth in vivo. Surprisingly, HSC function and maintenance of hematopoiesis in vivo was preserved despite these substantial cell-extrinsic changes. These data have implications for therapeutic strategies to target Rac signaling in HSC mobilization and in the treatment of leukemia and provide clarification to our evolving concepts of HSC-HM interactions.

scholarly journals Cartilage Ablation of Sirt1 Causes Inhibition of Growth Plate Chondrogenesis by Hyperactivation of mTORC1 Signaling

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 3001-3017 ◽  
Author(s):  
Xinxin Jin ◽  
Xiaomin Kang ◽  
Liting Zhao ◽  
Mao Xu ◽  
Tianping Xie ◽  
...  
Keyword(s):  
Growth Plate ◽  
Growth Retardation ◽  
Bone Growth ◽  
Bone Development ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Sirtuin 1 ◽  
Growth Plate Chondrocytes ◽  
Mtorc1 Signaling

Abstract A growing body of evidence implies a pivotal role of sirtuin-1 (Sirt1) in chondrocyte function and homeostasis; however, its underlying mechanisms mediating chondrogenesis, which is an essential process for physiological skeletal growth, are still poorly understood. In the current study, we generated TamCartSirt1−/− [Sirt1 conditional knockout (cKO)] mice to explore the role of Sirt1 during postnatal endochondral ossification. Compared with control mice, cKO mice exhibited growth retardation associated with inhibited chondrocyte proliferation and hypertrophy, as well as activated apoptosis. These effects were regulated by hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) signaling, and thereby inhibition of autophagy and induction of endoplasmic reticulum stress in growth plate chondrocytes. IP injection of the mTORC1 inhibitor rapamycin to mice with Sirt1 deletion partially neutralized such inhibitory effects of Sirt1 ablation on longitudinal bone growth, indicating the causative link between SIRT1 and mTORC1 signaling in the growth plate. Mechanistically, SIRT1 interacted with tuberous sclerosis complex 2 (TSC2), a key upstream negative regulator of mTORC1 signaling, and loss of Sirt1 inhibited TSC2 expression, resulting in hyperactivated mTORC1 signaling in chondrocytes. In conclusion, our findings suggest that loss of Sirt1 may trigger mTORC1 signaling in growth plate chondrocytes and contributes to growth retardation, thus indicating that SIRT1 is an important regulator during chondrogenesis and providing new insights into the clinical potential of SIRT1 in bone development.

scholarly journals Recent Insights into Long Bone Development: Central Role of Hedgehog Signaling Pathway in Regulating Growth Plate

2019 ◽  
Vol 20 (23) ◽  
pp. 5840 ◽  
Author(s):  
Haraguchi ◽  
Kitazawa ◽  
Kohara ◽  
Ikedo ◽  
Imai ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Growth Plate ◽  
Bone Development ◽  
Growth Period ◽  
Long Bone ◽  
Endochondral Bone Formation ◽  
Molecular Characteristics ◽  
Growth Plate Chondrocytes ◽  
Wide Range

The longitudinal growth of long bone, regulated by an epiphyseal cartilaginous component known as the “growth plate”, is generated by epiphyseal chondrocytes. The growth plate provides a continuous supply of chondrocytes for endochondral ossification, a sequential bone replacement of cartilaginous tissue, and any failure in this process causes a wide range of skeletal disorders. Therefore, the cellular and molecular characteristics of the growth plate are of interest to many researchers. Hedgehog (Hh), well known as a mitogen and morphogen during development, is one of the best known regulatory signals in the developmental regulation of the growth plate. Numerous animal studies have revealed that signaling through the Hh pathway plays multiple roles in regulating the proliferation, differentiation, and maintenance of growth plate chondrocytes throughout the skeletal growth period. Furthermore, over the past few years, a growing body of evidence has emerged demonstrating that a limited number of growth plate chondrocytes transdifferentiate directly into the full osteogenic and multiple mesenchymal lineages during postnatal bone development and reside in the bone marrow until late adulthood. Current studies with the genetic fate mapping approach have shown that the commitment of growth plate chondrocytes into the skeletal lineage occurs under the influence of epiphyseal chondrocyte-derived Hh signals during endochondral bone formation. Here, we discuss the valuable observations on the role of the Hh signaling pathway in the growth plate based on mouse genetic studies, with some emphasis on recent advances.

scholarly journals Expression of aromatase in the human growth plate

2001 ◽  
Vol 27 (2) ◽  
pp. 249-253 ◽  
Author(s):  
OK Oz ◽  
R Millsaps ◽  
R Welch ◽  
J Birch ◽  
JE Zerwekh
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Human Growth ◽  
Adolescent Male ◽  
Long Bone ◽  
Rt Pcr ◽  
Chain Reaction ◽  
Growth Plates ◽  
Estrogen Production ◽  
Polymerase Chain

Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.

Isolation, Culture and Identification of Bovine Skeletal Stem Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 2337-2345
Author(s):  
Junhui Lai ◽  
Qin Yang ◽  
Ruining Liang ◽  
Weijun Guan ◽  
Xiuxia Li
Keyword(s):  
Stem Cells ◽  
Cell Surface ◽  
Bone Formation ◽  
Growth Plate ◽  
Bone Development ◽  
Long Bone ◽  
Biological Characterization ◽  
Self Renewal ◽  
And Cartilage

The growth plate is essential in long bone formation and contains a wealth of skeletal stem cells (SSCs). Though the origin and the mechanism for SSCs generation remain uncertain, recent studies demonstrate the transition from cartilage to bone that in the lineage for bone development. SSCs possesses the ability to differentiate into bone and cartilage in vitro. In this research, we aimed to isolate and culture the skeletal stem cells from bovine cattle and then studied its biological characterization. The results showed that these bovine SSCs are positive for PDPN+CD73+CD164+CD90+CD44+ cell surface bio-markers, they are capable of self-renewal and differentiation. Our dates proved that SSCs exists in bovine’s long bone.

scholarly journals Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model

2019 ◽  
Author(s):  
Holly Dupuis ◽  
Michael Andrew Pest ◽  
Ermina Hadzic ◽  
Thin Xuan Vo ◽  
Daniel B. Hardy ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Long Bone ◽  
Tunel Staining ◽  
Long Bones ◽  
Micro Computed Tomography ◽  
Computed Tomography Scanning ◽  
Calcified Tissue ◽  
Trap Staining ◽  
Tomography Scanning

AbstractLongitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.

scholarly journals RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate

2014 ◽  
Vol 53 (1) ◽  
pp. T1-T9 ◽  
Author(s):  
Julian C Lui ◽  
Ola Nilsson ◽  
Jeffrey Baron
Keyword(s):  
Growth Plate ◽  
Bone Morphogenetic Proteins ◽  
Bone Growth ◽  
Association Studies ◽  
Expression Patterns ◽  
Human Growth ◽  
Cytokine Signaling ◽  
Genome Wide Association Studies ◽  
Paracrine Factors ◽  
Large Numbers

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

scholarly journals Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vivi F. H. Jensen ◽  
Anne-Marie Mølck ◽  
Ingrid B. Bøgh ◽  
Jette Nowak ◽  
Birgitte M. Viuff ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Skeletal Development ◽  
Long Bone ◽  
Structural Protein ◽  
Pregnant Rats ◽  
Growth Plates ◽  
Chondrocyte Maturation ◽  
Foetal Growth ◽  
Histopathologic Changes

AbstractMaternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.

scholarly journals Analysis of short-term treatment with the phosphodiesterase type 5 inhibitor tadalafil on long bone development in young rats

2018 ◽  
Vol 315 (4) ◽  
pp. E446-E453 ◽  
Author(s):  
Luqiang Wang ◽  
Haoruo Jia ◽  
Robert J. Tower ◽  
Michael A. Levine ◽  
Ling Qin
Keyword(s):  
Growth Plate ◽  
Time Course ◽  
Bone Growth ◽  
Bone Structure ◽  
Primary Cultures ◽  
Long Bone ◽  
Short Term ◽  
Short Term Treatment ◽  
Bone Properties ◽  
Phosphodiesterase Type 5 Inhibitor

Cyclic GMP (cGMP) is an important intracellular regulator of endochondral bone growth and skeletal remodeling. Tadalafil, an inhibitor of the phosphodiesterase (PDE) type 5 (PDE5) that specifically hydrolyzes cGMP, is increasingly used to treat children with pulmonary arterial hypertension (PAH), but the effect of tadalafil on bone growth and strength has not been previously investigated. In this study, we first analyzed the expression of transcripts encoding PDEs in primary cultures of chondrocytes from newborn rat epiphyses. We detected robust expression of PDE5 as the major phosphodiesterase hydrolyzing cGMP. Time-course experiments showed that C-type natriuretic peptide increased intracellular levels of cGMP in primary chondrocytes with a peak at 2 min, and in the presence of tadalafil the peak level of intracellular cGMP was 37% greater ( P < 0.01) and the decline was significantly attenuated. Next, we treated 1-mo-old Sprague Dawley rats with vehicle or tadalafil for 3 wk. Although 10 mg·kg−1·day−1 tadalafil led to a significant 52% ( P < 0.01) increase in tissue levels of cGMP and a 9% reduction ( P < 0.01) in bodyweight gain, it did not alter long bone length, cortical or trabecular bone properties, and histological features. In conclusion, our results indicate that PDE5 is highly expressed in growth plate chondrocytes, and short-term tadalafil treatment of growing rats at doses comparable to those used in children with PAH has neither obvious beneficial effect on long bone growth nor any observable adverse effect on growth plate structure and trabecular and cortical bone structure.

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