Growth Plate Development Research Articles

Pthlha and mechanical force control early patterning of growth zones in the zebrafish craniofacial skeleton.

ABSTRACTSecreted signals in patterning systems often induce repressive signals that shape their distributions in space and time. In developing growth plates (GPs) of endochondral long bones, Parathyroid hormone-like hormone (Pthlh) inhibits Indian hedgehog (Ihh) to form a negative-feedback loop that controls GP progression and bone size. Whether similar systems operate in other bones and how they arise during embryogenesis remain unclear. We show that Pthlha expression in the zebrafish craniofacial skeleton precedes chondrocyte differentiation and restricts where cells undergo hypertrophy, thereby initiating a future GP. Loss of Pthlha leads to an expansion of cells expressing a novel early marker of the hypertrophic zone (HZ), entpd5a, and later HZ markers, such as ihha, whereas local Pthlha misexpression induces ectopic entpd5a expression. Formation of this early pre-HZ correlates with onset of muscle contraction and requires mechanical force; paralysis leads to loss of entpd5a and ihha expression in the pre-HZ, mislocalized pthlha expression and no subsequent ossification. These results suggest that local Pthlh sources combined with force determine HZ locations, establishing the negative-feedback loop that later maintains GPs.

Uncovering pathways regulating chondrogenic differentiation of CHH fibroblasts

Mutations in the non-coding snoRNA component of mitochondrial RNA processing endoribonuclease (RMRP) are the cause of cartilage-hair hypoplasia (CHH). CHH is a rare form of metaphyseal chondrodysplasia characterized by disproportionate short stature and abnormal growth plate development. The process of chondrogenic differentiation within growth plates of long bones is vital for longitudinal bone growth. However, molecular mechanisms behind impaired skeletal development in CHH patients remain unclear. We employed a transdifferentiation model (FDC) combined with whole transcriptome analysis to investigate the chondrogenic transdifferentiation capacity of CHH fibroblasts and to examine pathway regulation in CHH cells during chondrogenic differentiation. We established that the FDC transdifferentiation model is a relevant in vitro model of chondrogenic differentiation, with an emphasis on the terminal differentiation phase, which is crucial for longitudinal bone growth. We demonstrated that CHH fibroblasts are capable of transdifferentiating into chondrocyte-like cells, and show a reduced commitment to terminal differentiation. We also found a number of key factors of BMP, FGF, and IGF-1 signalling axes to be significantly upregulated in CHH cells during the chondrogenic transdifferentiation. Our results support postulated conclusions that RMRP has pleiotropic functions and profoundly affects multiple aspects of cell fate and signalling. Our findings shed light on the consequences of pathological CHH mutations in snoRNA RMRP during chondrogenic differentiation and the relevance and roles of non-coding RNAs in genetic diseases in general.

Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice.

BackgroundOur recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear.Materials and methodsMice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice (Kindlin-2fl/fl; OsxCre) and control littermates were isolated and determined for their osteoblastic differentiation capacity.ResultsKindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity.ConclusionsOur study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice.The translational potential of this articleThis study reveals that Kindlin-2 through its expression in osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.

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.

The effects of in ovo administered bisphenol A on tibial growth plate histology in chicken

The aim of this study was to determine of the effects of in ovo administered BPA on embryonic development of the tibial growth plate using histological methods in chickens. Three hundred and ten fertile eggs of Isa Brown laying parent stock were divided into five groups as untreated control, vehicle-injected control, 50, 100, and 250 μg/egg BPA. At the 13th, 18th, and 21st days of incubation, eggs were randomly opened from each group until 10 live embryos were obtained. Embryos were weighed and crown-rump length was measured. Tibial tissue samples were taken from embryos. Tibia weight, relative tibia weight and tibia length were determined. Tissue samples were fixed in 10% buffered formalin solution. Sections were stained with Safranin O staining methods and zones in the growth plate were measured. Also, proliferating cell nuclear antigen (PCNA) was stained immunohistochemically. The mortality in the BPA treated groups was higher than untreated control group. The results have revealed that mean relative embryo weights, crown-rump length, mean tibia weight, relative tibia weight, and tibia length of BPA treated groups were significantly lower when compared to the untreated control and vehicle-injected control groups. Also, proliferative zone get significantly narrowed, whereas the transitional and hypertrophic zone thickened and PCNA positive chondrocytes increased in growth plate of BPA treated groups. These results have suggested that developmental exposure to BPA adversely affected development of the tibial growth plate.

Enchondromatosis and Growth Plate Development.

Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide an overview of recent progress in understanding causative mutations for enchondroma, dysregulated signaling and metabolic pathways in enchondroma, and the progression from enchondroma to malignant chondrosarcoma. Several signaling pathways that regulate chondrocyte differentiation are dysregulated in enchondromas. Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common findings in enchondromas. Mechanisms including metabolic regulation, epigenetic regulation, and altered signaling pathways play a role in enchondroma formation and progression. Multiple pathways regulate growth plate development in a coordinated manner. Deregulation of the process can result in chondrocytes failing to undergo differentiation and the development of enchondroma.

Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth.

Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1-/- mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1-deficient chondrocytes. PTH (1-34) enhanced and PTH (7-34) attenuated cell proliferation, cAMP signaling, cAMP response element-binding protein (CREB) phosphorylation, and cell metabolic activity in Phlpp1-inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1-deficient mice, Phlpp1-/- mice were injected with Pth1r ligand PTH (7-34) daily for the first 4 weeks of life. PTH (7-34) reversed the abnormal growth plate and long-bone growth phenotypes of Phlpp1-/- mice but did not rescue deficits in bone mineral density or trabecular number. These results show that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1-/- chondrocytes and shorter bones in Phlpp1-deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth. © 2021 American Society for Bone and Mineral Research (ASBMR).

Role of iRhoms 1 and 2 in Endochondral Ossification.

Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification.

Screening of the SHOX/PAR1 region using MLPA and miRNA expression profiling in a group of Egyptian children with non-syndromic short stature

BackgroundShort stature is defined as a body height below the third percentile, based on chronological age, or 2 standard deviations (SD) below the national height standard. The prevalence of short stature is around 2% of children worldwide. Several gene deficiencies have been associated with the etiology of short stature. The SHOX is an important candidate gene for short stature, as its haploinsufficiency underlies syndromic and non-syndromic short stature. Partial and complete duplications of SHOX have been reported in patients with short stature. Proper genetic diagnosis of these children allows for appropriate therapeutic approaches to be administered. Since copy number variation (CNV) is a possible mechanism of interhuman variability and pathogenic disease, the multiplex ligation-dependent probe amplification technique (MLPA) can be used as an initial screening technique. Cartilage tissue expresses specific microRNAs (miRNAs), which play an essential role in the regulation of chondrocyte proliferation and differentiation during growth plate development. We aimed to assess the SHOX/PAR1 region using CNV profiling for non-syndromic short stature in Egyptian children with and without growth hormone deficiency using the MLPA technique and expression profiling of miR-1, miR-15a, and miR-140 using quantitative real-time polymerase chain reaction (qRT-PCR) in a group of Egyptian children with non-syndromic short stature.ResultsOf the fifty cases included in this study, different CNVs were detected in ten children (20%), in/outside the SHOX region. Moreover, in children with short stature, the expression level of miRNA-140 was significantly different from that of healthy controls.ConclusionsThis is one of the first studies that have assessed CNVs in the SHOX/PAR1 region in a group of Egyptian children with short stature. MLPA analysis of SHOX/PAR1 identified different CNVs in children with non-syndromic short stature, suggesting that the MLPA should be used as an initial screening technique in short children, as proper genetic diagnosis of these children leads to implementation of the appropriate therapeutic approach. Alterations in the levels of miRNA-140 in children with short stature suggest that changes in the expression levels of this miRNA are associated with the pathogenesis of short stature.

Gamma Aminobutyric Acid-Enriched Fermented Oyster (Crassostrea gigas) Increases the Length of the Growth Plate on the Proximal Tibia Bone in Sprague-Dawley Rats.

Bone growth during childhood and puberty determines an adult’s final stature. Although several prior studies have reported that fermented oyster (FO) consisting of a high amount of gamma aminobutyric acid can be attributed to bone health, there is no research on the efficacy of FO on growth regulation and the proximal tibial growth plate. Therefore, in this study, we investigated the effect of FO oral administration on hepatic and serum growth regulator levels and the development of the proximal tibial growth plate in young Sprague-Dawley rats. Both oral administration of FO (FO 100, 100 mg/kg FO and FO 200, 200 mg/kg FO) and subcutaneous injection of recombinant human growth hormone (rhGH, 200 μg/kg of rhGH) for two weeks showed no toxicity. Circulating levels of growth hormone (GH) significantly increased in the FO 200 group. The expression and secretion of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) were enhanced by FO administration. FO administration promoted the expression of bone morphogenic proteins IGF-1 and IGFBP-3 in the proximal tibial growth plate. This positive effect of FO resulted in incremental growth of the entire plate length by expanding the proliferating and hypertrophic zones in the proximal tibial growth plate. Collectively, our results suggested that oral administration of FO is beneficial for bone health, which may ultimately result in increased height.

Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia

BackgroundLong bones of limbs are formed through endochondral bone formation, which depends on the coordinated development of growth plates. Our previous studies have demonstrated that dysfunction of mitogen-activated protein kinase 7 (MAPK7) can cause skeletal dysplasia. However, little is known about the role of MAPK7 in the regulation of proliferation and differentiation of chondrocytes during growth plate development.ResultsAblation of MAPK7 expression in chondrocytes led to growth restriction, short limbs and bone mass loss in postnatal mice. Histological studies revealed that MAPK7 deficiency increased the apoptosis and decreased the proliferation of chondrocytes in the center of the proliferative layer, where the most highly hypoxic chondrocytes are located. Accordingly, hypertrophic differentiation markers were downregulated in the central hypertrophic layer, beneath the site where abnormal apoptosis was observed. Simultaneously, we demonstrated that hypoxic adaptation and hypoxia-induced activation of hypoxia-inducible factor 1 subunit α (HIF1α) were impaired when MAPK7 could not be activated normally in primary chondrocytes. Concomitantly, vascular invasion into epiphyseal cartilage was inhibited when Mapk7 was deleted.ConclusionsWe demonstrated that MAPK7 is necessary for maintaining proliferation, survival, and differentiation of chondrocytes during postnatal growth plate development, possibly through modulating HIF1α signaling for adaptation to hypoxia. These results indicate that MAPK7 signaling might be a target for treatment of chondrodysplasia.

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents.

Restriction of physical growth and development is a known problem in patients with juvenile idiopathic arthritis (JIA). However, the effect of medical treatment for JIA on skeletal growth in affected children has not been properly investigated. We, therefore, hypothesize that naproxen and methotrexate (MTX) affect endochondral ossification and will lead to reduced skeletal development. Treatment of ATDC5 cells, an in vitro model for endochondral ossification, with naproxen or MTX resulted in increased chondrogenic but decreased hypertrophic differentiation. In vivo, healthy growing C57BL/6 mice were treated with naproxen, MTX, or placebo for 10 weeks. At 15 weeks postnatal, both the length of the tibia and the length of the femur were significantly reduced in the naproxen‐ and MTX‐treated mice compared to their controls. Growth plate analysis revealed a significantly thicker proliferative zone, while the hypertrophic zone was significantly thinner in both experimental groups compared to their controls, comparable to the in vitro results. Micro‐computed tomography analysis of the subchondral bone region directly below the growth disc showed significantly altered bone microarchitecture in naproxen and MTX groups. In addition, the involvement of the PTHrP‐Ihh loop in naproxen‐ and MTX‐treated cells was shown. Overall, these results demonstrate that naproxen and MTX have a profound effect on endochondral ossification during growth plate development, abnormal subchondral bone morphology, and reduced bone length. A better understanding of how medication influences the development of the growth plate will improve understanding of endochondral ossification and reveal possibilities to improve the treatment of pediatric patients.

GR/Sp3/HDAC1/UGDH signaling participated in the maternal dexamethasone-induced dysplasia of the rat fetal growth plate.

Maternal dexamethasone decreases the body length of the newborn. However, whether dexamethasone inhibits the development of the growth plate of the fetal long bone is still unknown. Here, we found that lengths of fetal femur and growth plate were both shorter in the fetuses with maternal dexamethasone (0.2mg/kg.d from gestation day 9 to 20), with a decreased proteoglycan content of the growth plate in the fetal rat. Notable decreases in both the gene expression and H3K9 acetylation of UDP-glucose dehydrogenase (Ugdh) gene, which codes a key enzyme in the proteoglycan biosynthesis in the chondrocyte, were also observed. Meanwhile, up-regulation of glucocorticoid receptor (GR), specific protein 3 (Sp3), and histone deacetylase 1 (Hdac1) gene expression were detected in the fetal growth plate. Similar changes were also observed in the chondrogenic rat bone marrow stromal cells (BMSCs) with excessive exogenous dexamethasone. However, antagonizing GR with RU486 and silencing Hdac1 or Sp3 with specific siRNAs could all stimulate the H3K9 acetylation and gene expression of Ugdh previously inhibited by dexamethasone. Meanwhile, dexamethasone also induced the nuclear translocation of GR, which further directly bound to the Ugdh promoter and interacted with HDAC1 and Sp3, respectively. Collectively, our study revealed that maternal dexamethasone induced the direct binding of GR to the Ugdh promoter of the chondrocyte in the rat fetal growth plate, which recruited HDAC1 and Sp3, induced deacetylation of the H3K9, and subsequently inhibited Ugdh gene expression. Such changes further led to attenuated proteoglycan synthesis in the developing chondrocyte and therefore disrupted the development of growth plate and fetal long bone.

Lactobacillus rhamnosus JYLR-005 Prevents Thiram-Induced Tibial Dyschondroplasia by Enhancing Bone-Related Growth Performance in Chickens.

Tibial dyschondroplasia (TD) is a leg disorder caused by the abnormal development of the tibia in fast-growing poultry. Lactobacillus rhamnosus (L. rhamnosus) strains have been reported to have effects on increasing bone growth and improving osteoporosis in animals. However, whether L. rhamnosus JYLR-005 can improve bone growth in TD chickens remains unclear. In this study, we noted that L. rhamnosus JYLR-005 could not reduce the suppression of the production performance of TD broilers (p > 0.05) but had a slight protective effect on the broiler survival rate (χ2 = 5.571, p = 0.062). However, for thiram-induced TD broiler chickens, L. rhamnosus JYLR-005 could promote tibia growth by increasing tibia-related parameters, including the tibia weight (day 11, p = 0.040), tibia length (day 15, p = 0.013), and tibia mean diameter (day 15, p = 0.035). Moreover, L. rhamnosus JYLR-005 supplementation improved the normal growth and development of the tibial growth plate by maintaining the morphological structure of the chondrocytes and restored the balance of calcium and phosphorus. Taken together, these findings provide a proof of principle that L. rhamnosus JYLR-005 may represent a therapeutic strategy to treat leg disease in chickens.

Growth plate gene involment and isolated short stature

Short stature is a common clinical presentation, thus it is widely accepted that it is a polygenic trait. However, genome wide association and next generation sequencing studies have recently challenged this view, suggesting that many of the children classified as idiopathic short stature could instead have monogenic defects. Linear growth is determined primarily by chondrogenesis at the growth plate. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is perfectly coordinated by complex networks of local paracrine and endocrine factors. Alterations in genes which control growth plate development can explain a large number of cases of isolated short stature, allowing an etiological diagnosis. We reviewed recent data on the genetic alterations in fundamental cellular processes, paracrine signaling, and cartilage matrix formation associated with impaired growth plate chondrogenesis. In particular we focused on growth plate gene involvement in nonsyndromic short stature. The identification of genetic basis of growth failure will have a significant impact on the care of children affected with short stature.

DDB1 promotes the proliferation and hypertrophy of chondrocytes during mouse skeleton development

The proliferation and hypertrophy of chondrocytes play important roles in endochondral ossification, which is tightly regulated during skeleton development. However, the regulation mechanism remains largely unknown. Here we show that DDB1 (Damaged DNA Binding Protein 1) has a critical function in the development of growth plates. Using chondrocyte-specific DDB1 knockout mice, we found that DDB1 deletion in chondrocytes results in dwarfism due to the aberrant skeleton development. The structure of growth plate in tibia becomes disordered at P21, not in femur. But at P70, the changes are severer in femur than tibia. Chondrocyte proliferation and differentiation are attenuated and asynchronous in both tibia and femur at P7 and P21. Furthermore, DDB1 deficiency induces p27 upregulation and subsequent cell cycle arrest in primary chondrocytes. Therefore, our data reveal that DDB1 is essential for the skeleton development by controlling chondrocyte proliferation and differentiation.

TGFβ as a gatekeeper of BMP action in the developing growth plate.

The ligands that comprise the Transforming Growth Factor β superfamily highly govern the development of the embryonic growth plate. Members of this superfamily activate canonical TGFβ and/or BMP (Bone Morphogenetic Protein) signaling pathways. How these pathways interact with one another is an area of active investigation. These two signaling pathways have been described to negatively regulate one another through crosstalk involving Smad proteins, the primary intracellular effectors of canonical signaling. More recently, a mechanism for regulation of the BMP pathway through TGFβ and BMP receptor interactions has been described. Here in this review, we demonstrate examples of how TGFβ is a gatekeeper of BMP action in the developing growth plate at both the receptor and transcriptional levels.

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

Maternal 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.

Upper Airway Obstruction Elicited Energy Imbalance Leads to Growth Retardation that Persists after the Obstruction Removal

Upper airway obstruction can lead to growth retardation by unclear mechanisms. We explored the effect of upper airway obstruction in juvenile rats on whole-body energy balance, growth plate metabolism, and growth. We show that after seven weeks, obstructed animals’ ventilation during room air breathing increased, and animals grew less due to abnormal growth plate metabolism. Increased caloric intake in upper airway-obstructed animals did not meet increased energy expenditure associated with increased work of breathing. Decreased whole-body energy balance induced hindrance of bone elongation following obstruction removal, and array pathways regulating growth plate development and marrow adiposity. This is the first study to show that rapidly growing animals cannot consume enough calories to maintain their energy homeostasis, leading to an impediment in growth in the effort to save energy.

ROR2 promotes the epithelial-mesenchymal transition by regulating MAPK/p38 signaling pathway in breast cancer.

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a tyrosine-protein kinase receptor highly implicated in the growth plate and cartilage development, which may be involved in epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells. Although ROR2 is known to promote the migration of BC cells, the detailed mechanism of this event is still not clear. Here, we found that ROR2 expression was significantly increased in BC lymphatic metastatic tissue as well as BC samples compared to normal adjacent breast tissues. A higher expression of ROR2 in MDA-MB-231 and a lower expression of ROR2 in MCF-7 cells were observed. MDA-MB-231-siROR2 cells with ROR2 knockdown inhibited MDA-MB-231 cell invasion, migration, and clonal formation, while MCF-7-OvROR2 cells with overexpression showed the opposite results. The underlying mechanisms involved in ROR2-induced EMT in MDA-MB-231 and MCF-7 cells were further investigated. ROR2 may activate EMT progression in BC cells by altering MAPK kinase 3/6 (MKK3/6) expression. The expressions of transforming growth factor-β, matrix metalloproteinase-2 (MMP-2), and MMP-9, which were related to tumor cell invasion activities, were notably increased in MCF-7-OvROR2 cells. The EMT markers, including snail, N-cadherin, tissue inhibitor of metalloproteinases-1, and vimentin, were significantly upregulated in MCF-7-OvROR2 cells. On the contrary, E-cadherin was obviously reduced expressed in MCF-7-OvROR2 cells. ROR2 may regulate the malignant phenotype of BC cells possibly via activation of mitogen-activated protein kinase (MAPK)/p38 signaling pathway. Collectively, ROR2 promotes BC carcinogenesis by mediating the MAPK/p38 pathway, which is independent of Wnt5α.