Restraint upon Embryonic Metatarsal Ex Vivo Growth by Hydrogel Reveals Interaction between Quasi-Static Load and the mTOR Pathway

Mechanical cues play a vital role in limb skeletal development, yet their influence and underpinning mechanisms in the regulation of endochondral ossification (EO) processes are incompletely defined. Furthermore, interactions between endochondral growth and mechanics and the mTOR/NF-ĸB pathways are yet to be explored. An appreciation of how mechanical cues regulate EO would also clearly be beneficial in the context of fracture healing and bone diseases, where these processes are recapitulated. The study herein addresses the hypothesis that the mTOR/NF-ĸB pathways interact with mechanics to control endochondral growth. To test this, murine embryonic metatarsals were incubated ex vivo in a hydrogel, allowing for the effects of quasi-static loading on longitudinal growth to be assessed. The results showed significant restriction of metatarsal growth under quasi-static loading during a 14-day period and concentration-dependent sensitivity to hydrogel-related restriction. This study also showed that hydrogel-treated metatarsals retain their viability and do not present with increased apoptosis. Metatarsals exhibited reversal of the growth-restriction when co-incubated with mTOR compounds, whilst it was found that these compounds showed no effects under basal culture conditions. Transcriptional changes linked to endochondral growth were assessed and downregulation of Col2 and Acan was observed in hydrogel-treated metatarsi at day 7. Furthermore, cell cycle analyses confirmed the presence of chondrocytes exhibiting S-G2/M arrest. These data indicate that quasi-static load provokes chondrocyte cell cycle arrest, which is partly overcome by mTOR, with a less marked interaction for NF-ĸB regulators.

Surgical Treatment of Juvenile Femoral Head Epiphysiolysis in Children

To optimize the anatomical and functional surgical treatment results in patients with early (I-II) stages of juvenile femoral head epiphysiolysis both pre- and postoperative data of clinical, x-ray and magnetic-resonance examinations were analyzed for 120 patients aged 11 - 15 years. Maximum follow up period after surgical interventions, i.e. femoral head epiphysiodesis (n=60) and femoral head epiphysis fixation (n=60) made up 23 and 3 years, respectively. It was shown that surgical intervention for the fixation of femoral head epiphysis ensured reliable stability of the epiphysis preventing the latter from displacement development and progression, and did not exert significant influence upon either femoral neck and head endochondral growth or the length of the upper extremity.

Surgical Treatment of Juvenile Femoral Head Epiphysiolysis in Children

To optimize the anatomical and functional surgical treatment results in patients with early (I-II) stages of juvenile femoral head epiphysiolysis both pre- and postoperative data of clinical, x-ray and magnetic-resonance examinations were analyzed for 120 patients aged 11 - 15 years. Maximum follow up period after surgical interventions, i.e. femoral head epiphysiodesis (n=60) and femoral head epiphysis fixation (n=60) made up 23 and 3 years, respectively. It was shown that surgical intervention for the fixation of femoral head epiphysis ensured reliable stability of the epiphysis preventing the latter from displacement development and progression, and did not exert significant influence upon either femoral neck and head endochondral growth or the length of the upper extremity.

Pharmacodynamic responses of plasma and tissue C-type natriuretic peptide to GH: correlation with linear growth in GH-deficient rats

Studies from genetic modification and spontaneous mutations show that C-type natriuretic peptide (CNP) signalling plays an essential part in postnatal endochondral growth, but measurement of CNP proteins and changes in their abundance in tissues and plasma during normal growth has not been reported. Using rodent pups with GH deficiency, we now describe the pharmacodynamic response of CNP and rat amino-terminal proCNP (NTproCNP) in plasma and tissues, and relate these to changes in linear growth (nose–tail length, tibial length and tibial growth plate width) during the course of 1 week of GH or saline (control) administration. Compared with saline, significant increases in plasma and tissue CNP forms were observed after 24 h in GH-treated pups and before any detectable change in linear growth. Whereas CNP abundance was increased in most tissues (muscle, heart and liver) by GH, enrichment was the greatest in extracts from growth plates and kidney. Plasma and tissue concentrations in GH-treated pups were sustained or further increased at 1 week when strong positive associations were found between plasma NTproCNP and linear growth or tissue concentrations. High content of NTproCNP in kidney tissue strongly correlated with plasma concentrations, which is consistent with previous data showing renal extraction of the peptide. In showing a prompt and significant increase in CNP in tissues driving normal endochondral growth, these findings provide further rationale for CNP agonists in the treatment of growth disorders resistant to current therapies and support the use of CNP concentrations as biomarkers of linear growth.