Beyond Growth Hormone: Association of Short Stature Types and Growth Hormones With Scoliosis.

STUDY DESIGN: Cross-sectional and retrospective cohort study. OBJECTIVE: We investigated the effect of 3 types of short stature [partial growth hormone deficiency (GHD), GHD, and idiopathic short stature (ISS)] and recombinant human growth hormone (rhGH) therapy on scoliosis. SUMMARY OF BACKGROUND DATA: In short stature, rhGH is widely used and the concentration of growth hormone varies among types. The epidemiologic characteristics of scoliosis and the role of rhGH in scoliosis remain unclear. PATIENTS AND METHODS: A cross-sectional study was conducted among 3896 patients with short stature (partial GHD, GHD, and ISS), and a 1:1 age and sex-matched control group with preexisting whole-spine radiographs. The cohort study included 2605 subjects who underwent radiography more than twice to assess scoliosis development, progression, and the need for bracing and surgery. Adjusted logistic regression was used to assess differences in the prevalence of scoliosis among patients with partial GHD, GHD, ISS, and controls. The Kaplan-Meier method was used to analyze the time course of scoliosis development and progression. Cox regression was applied to assess the independent factors related to scoliosis development and progression. Mendelian randomization analyses were also performed. RESULTS: Compared with controls, patients with short stature had a higher incidence of scoliosis (34.47% in partial GHD, 31.85% in GHD, 32.94% in ISS vs . 8.83% in control, P < 0.001), a higher risk of scoliosis development [hazard ratio (HR) = 1.964 in partial GHD, P < 0.001; HR = 1.881 in GHD, P = 0.001; HR = 1.706 in ISS, P = 0.001), but not a higher risk of progression, brace, or surgery. Among the 3 types of short stature, there were no differences in the incidence, development, and progression of scoliosis or the need for bracing or surgery. RhGH treatment increased the risk of scoliosis development in each short-stature group (HR = 2.673 in partial GHD, P < 0.001; HR = 1.924 in GHD, P = 0.049; HR = 1.564 in ISS, P = 0.004). Vitamin D supplementation was protective against scoliosis development (HR = 0.456 in partial GHD, P = 0.003; HR = 0.42 in GHD, P = 0.013; HR = 0.838 in ISS, P = 0.257). CONCLUSIONS: More attention should be paid to the spinal curve in patients with partial GHD, GHD, or ISS. For short stature treated with rhGH, the risk of scoliosis development was increased. Vitamin D supplementation may be beneficial for prevention. LEVEL OF EVIDENCE: Level III.

HTRA1 from OVX rat osteoclasts causes detrimental effects on endplate chondrocytes through NF-κB.

Endplate osteochondritis is considered one of the major causes of intervertebral disc degeneration (IVDD) and low back pain. Menopausal women have a higher rate of endplate cartilage degeneration than similarly aged men, but the related mechanisms are still unclear. Subchondral bone changes, mainly mediated by osteoblasts and osteoclasts, are considered an important reason for the degeneration of cartilage. This work explored the role of osteoclasts in endplate cartilage degeneration, as well as its underlying mechanisms. A rat ovariectomy (OVX) model was used to induce estrogen deficiency. Our experiments indicated that OVX significantly promoted osteoclastogenesis and anabolism and catabolism changes in endplate chondrocytes. OVX osteoclasts cause an imbalance between anabolism and catabolism in endplate chondrocytes, as shown by a decrease in anabolic markers such as Aggrecan and Collagen II, and an increase in catabolic markers such as a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinases (MMP13). Osteoclasts were also confirmed in this study to be able to secrete HtrA serine peptidase 1 (HTRA1), which resulted in increased catabolism in endplate chondrocytes through the NF-κB pathway under estrogen deficiency. This study demonstrated the involvement and mechanism of osteoclasts in the anabolism and catabolism changes of endplate cartilage under estrogen deficiency, and proposed a new strategy for the treatment of endplate osteochondritis and IVDD by targeting HTRA1.

Associations of Homocysteine, Folate, and Vitamin B12 with Osteoarthritis: A Mendelian Randomization Study.

Homocysteine, inversely related to folate and vitamin B12, is an independent risk factor for several age-related disorders. However, little is known about the association of homocysteine and related vitamins with osteoarthritis (OA). This study aimed to elucidate the potential causal effects of homocysteine, folate, and vitamin B12 on site- and gender-specific OA by applying the two-sample Mendelian randomization (MR) approach. Genetically predicted homocysteine showed adverse effects on overall OA (95% confidence interval (CI): 1.044-1.155), knee OA (95% CI: 1.000-1.167), hip OA (95% CI: 1.057-1.297), and spine OA (95% CI: 1.017-1.216). Genetically predicted folate showed protective effects on overall OA (95% CI: 0.783-0.961) and spine OA (95% CI: 0.609-0.954). Folate (95% CI: 0.887-1.004) and vitamin B12 (95% CI: 0.886-1.009) showed a protective trend against knee OA. The patterns of associations were site and gender specific. In conclusion, homocysteine had adverse effects on OA, especially on OA at weight-bearing joints and in females. Folate and vitamin B12 had protective effects on OA. Homocysteine-lowering interventions may be a potential option in the treatment and prevention of OA.

Idiopathic short stature and scoliosis in children treated with growth hormone.

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study. A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery. In the cross-sectional study, there was an unexpectedly higher prevalence of scoliosis (33.1% (681/2,053) vs 8.52% (350/4,106)) in children with idiopathic short stature compared with controls (odds ratio 3.722; p < 0.001), although most cases were mild. In the longitudinal study, children with idiopathic short stature had a higher risk of the development and progression of scoliosis than the controls. Among children with idiopathic short stature without scoliosis at baseline, treatment with growth hormone significantly increased the risk of developing scoliosis (p = 0.015) and the need for bracing (p < 0.001). Among those with idiopathic short stature and scoliosis at baseline, treatment with growth hormone did not increase the risk of progression of the scoliosis, the need for bracing, or surgery. The impact of treatment with growth hormone on scoliosis in children with idiopathic short stature was considered controllable. However, physicians should pay close attention to the assessment of spinal curves in these children.

Effectiveness of Oxygen during Sintering of Silver Thin Films Derived by Nanoparticle Ink.

Silver nanoparticle (NP) inks have been widely used in the ink-jet printing field because of their excellent properties during low-temperature sintering. However, the organic dispersant used to prevent the aggregation and sedimentation of NPs can hinder the sintering process and result in the high resistivity of sintered films. In this study, silver thin films derived from silver NP ink with polyvinylpyrrolidone (PVP) dispersant were sintered in different atmospheres of pure nitrogen, air, and pure oxygen. The effect of the oxygen content in the sintering atmosphere on the thermal properties of the ink, the electrical resistivity and microstructure of the sintered films, and the amount of organic residue were studied by using differential scanning calorimetry, the four-point probe method, scanning electron microscopy, Fourier transform infrared spectroscopy, etc. The mechanism of optimizing the film resistivity by influencing the decomposition of the PVP dispersant and the microstructure evolution of the silver thin films through the sintering atmosphere was discussed. The results demonstrated that an oxygen-containing atmosphere could be effective for silver NPs in two ways. First, the oxygen content could enhance the diffusion ability of silver atoms, thus accelerating the stage transition of microstructural evolution at low temperatures. Second, the oxygen content could enable the PVP to decompose at a temperature much lower than in conditions of pure nitrogen, thus helping to finalize the densification of a silver film with a low resistivity of 2.47 µΩ·cm, which is approximately 1.5-fold that of bulk silver. Our findings could serve as a foundation for the subsequent establishment of ink-jet printing equipment and the optimization of the sintering process for printing silver patterns on flexible substrates.

3D perfusion culture of mouse insulinoma in macro-porous scaffolds enhanced insulin production response.

To address the remaining issue of poor cell immobilization and insufficient mass transfer in scaffold-based tissue engineering approach for future islet transplantation, we employed a macro-porous poly-l-lactide (PLLA) scaffold immobilizing mouse insulinoma cells and studied its function toward an implantable pancreatic tissue in 7-day perfusion culture. The murine pancreatic ß cells could be immobilized in the PLLA scaffold at a high density of 107 cells per cm3 close to the estimated range in normal pancreas. The perfusion culture promoted the 3D cellular organization as observed with live/dead staining and histological staining. The insulin production was significantly enhanced in comparison with static 2D culture and 3D rotational suspension culture by two and six folds, respectively (p < 0.001). As enhanced insulin response was only observed where both the perfusion and 3D cellular organization were present, this could represent important elements in engineering a functional bioartificial pancreas.

Cycloastragenol and Astragaloside IV activate telomerase and protect nucleus pulposus cells against high glucose-induced senescence and apoptosis.

In diabetes-induced intervertebral disc degeneration (Db-IVDD), senescence and apoptosis of nucleus pulposus cells (NPCs) are major contributing factors. Telomere attrition and telomerase downregulation are some of the main reasons for senescence and eventual apoptosis. The derivatives of the Chinese herb Astragalus membranaceus, Cycloastragenol (CAG) and Astragaloside IV (AG-IV), are reportedly effective telomerase activators against telomere shortening; however, their effect in Db-IVDD have not been explored. The present study simultaneously investigated the regulation of these derivatives on senescence, apoptosis, telomeres and telomerase a model of high-glucose (HG)-induced stress using rat primary NPCs. The NPCs were stimulated with HG (50 mM) to evoke HG-induced stress, and the effects of CAG and AG-IV were observed on: i) The expression level of senescence marker p16; ii) ß-Gal staining; iii) the expression levels of apoptosis markers cleaved-caspase 3 (c-C3), BAX and Bcl-2; iv) telomerase activation with telomerase reverse transcriptase (TERT) mRNA and protein expression, while telomere length was measured with reverse transcription-quantitative PCR. Cell proliferation was determined using the Cell Counting Kit-8 assay. Results demonstrated an upregulation in the expression levels of p16, c-C3 and BAX, and increased ß-Gal staining; while the expression level of Bcl-2 was downregulated in a concentration-dependent manner. Pre-treatment of the NPCs with CAG and AG-IV downregulated the protein expression levels of p16, c-C3 and BAX, and decreased the percentage of ß-Gal and FITC staining; while upregulating the Bcl-2 expression. These effects protected the cells from HG stress-induced senescence and apoptosis. HG also downregulated the expression profile of TERT and shortened the telomere length in a glucose concentration-dependent manner. While pretreatment with CAG and AG-IV upregulated TERT expression and ameliorated the telomere attrition. CAG and AG-IV also increased cell proliferation and improved cell morphology in HG conditions. Overall, these findings indicated that CAG and AG-IV suppressed HG stress-induced senescence and apoptosis, in addition to enhancing telomerase activation and lengthening of the Telomere. Therefore, CAG and AG-IV prolonged the replicative capability and longevity of the NPCs and they have the potential to be therapeutic agents in Db-IVDD.

Puerarin suppresses inflammation and ECM degradation through Nrf2/HO-1 axis in chondrocytes and alleviates pain symptom in osteoarthritic mice.

Osteoarthritis (OA) is the most common degenerative joint disorder with no effective drugs. Puerarin is a dietary supplement that has wide-ranging pharmacological effects. This study aimed to investigate the effects of Puerarin on OA. The effects of Puerarin on apoptosis, extracellular matrix (ECM) metabolism, and inflammation-related factors were assessed; also, the nuclear factor-κB (NF-κB) signaling pathway and Nrf2/HO-1 (nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1) axis were evaluated to elucidate the working mechanism of Puerarin. Mice were fed with Puerarin to evaluate the therapeutic effect of Puerarin on Osteoarthritis in vivo. The results showed that Puerarin suppressed inflammatory mediators and apoptosis induced by IL-1ß treatment in chondrocytes, it may also suppress ECM degradation in IL-1ß treated chondrocytes. The mechanism study revealed that Nrf2/HO-1 pathway is involved in Puerarin induced inhibition of NF-κB signaling pathway. Finally, in vivo study demonstrated that Puerarin could postpone the progression of OA in mice and relieve the symptoms of pain. In conclusion, Puerarin may potentially alleviate OA progression, and the mechanism may relate to the Nrf2/HO-1 pathway regulation.

Xanthohumol suppresses inflammation in chondrocytes and ameliorates osteoarthritis in mice.

Osteoarthritis (OA), manifested as degeneration and damage of the articular cartilage is a progressive disease of joints. Previous studies have shown that extracellular matrix degradation and inflammation have quite a significant performance in the occurrence and development of OA. In various maladies, an anti-inflammatory effect has been demonstrated for Xanthohumol (XN); while OA is an inflammation related disease. The current in vivo and in vitro study aimed to investigate the therapeutic effect of XN on OA as well as its working mechanism. The results showed that XN has the capability to hinder the expression of nitric oxide synthase (INOS), IL-1ß-promoted inducible nitric oxide (NO), necrosis factor-α of tumor (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) in vitro. In addition, XN has been found to down-regulate the expression of matrix metalloproteinase-13 and prothrombin stimulated by IL-1ß and up-regulates type II collagen and Aggrecan expression. At the same time, it was discovered that XN activates nuclear factor (Nrf2) in chondrocytes stimulated by IL-1ß and inhibits nuclear factor B (NF-кB) signal transduction. The DMM model manifests that XN has an inhibitory impact on the progression of osteoarthritis and thus may be a candidate drug to slow down and delay the development of OA.