Distraction Osteogenesis in the Combined and Sequential Use of Transosseous and Intramedullary Osteosynthesis: Experimental Study

Background. The methods of “lengthening over the nail” (LON) and the sequential use of the external fixation and nailing in the option “lengthening and then the nail” (LATN) are characterized by ignoring non-observance of the formulated by G.A. Ilizarov is the most important condition for optimizing the osteogenesis process, namely, the preservation of medullary blood supply and osteogenic bone marrow tissue. At the same time, in clinical practice, there was no negative effect of the intramedullary nail on the formation of the regenerate. In experimental studies, the activation of periosteal bone formation during LON is noted. But the active periosteal bone formation detected in clinical practice with a sequential technique has not been confirmed by experimental studies.The aim of the study was to compare the organotypical rebuilding of the distraction regenerate during tibial lengthening in rabbits according to Ilizarov, over the intramedullary fixator and with the sequential use of the external fixation and nailing.Materials and Methods. The study was carried out on 54 mature rabbits of the Soviet Chinchilla breed, which were divided into 3 groups of 18 animals. In Gr-1 (control), the tibia was lengthened by 1 cm in a mini-Ilizarov apparatus at a rate of 1 mm per day for 4 sessions step. In Gr-2, the LATN technique was modeled. After the end of lengthening, an intramedullary fixator was implanted installed, the apparatus with the presence of wires only in the base supports was kept as an imitation of blocking the intramedullary fixator. In Gr-3, lengthening was performed over the intramedullary fixator; at the end of lengthening, the wires were left only in the base supports. The fixation period was is 30 days. The total duration of the experiment is 45 days. On the 10th, 15th, 20th, 30th, 45th day X-ray, CT and morphological studies were performed during the experiment.Results. In the experimental groups, a more pronounced periosteal bone formation in the area of regenerates was noted, while in Gr-3 (LON) cortical plates were formed mainly from the periosteal component, and in Gr-2 (LATN) wide cortical plates were formed from the intermediate and periosteal areas. In this group, the maximum densitometric density values are noted. Endosteal bone formation was preserved in all groups.Conclusion. The LON and LATN techniques, when compared with the classical Ilizarov lengthening, do not demonstrate any deficiency in the organotypical rebuilding of the bone tissue of the regenerates. All zones of bone formation are present, including endosteal, with intense periosteal bone formation. The most powerful bone structures are formed with the sequential use of the external fixation and nailing (LATN) in the form of the formation of wide cortical plates due to the intermediate and periosteal zones of the regenerate.

Oral Estradiol Impact on Mitigating Unloading-Induced Bone Loss in Ovary-Intact Rats

BACKGROUND: The impact of the spaceflight environment on endogenous estrogen production in female crewmembers and the resulting impact on other adaptations, like bone loss, is an under-investigated topic. Hence, we investigated the interaction of exogenous 17- estradiol (E2) treatment and disuse to test the hypothesis that E2 treatment would mitigate disuse-induced bone loss.METHODS: There were 40 virgin female Sprague-Dawley rats (5 mo old) randomized to placebo (PL; 0 ppm E2) or estrogen (E2; 10 ppm E2) treatments, delivered via custom-made rodent diets; half of each group was randomized to either weightbearing (WB) or hindlimb unloading (HU) for 39 d.RESULTS: We observed expected lower values after HU (615%) in volumetric BMD and cross-sectional areas at the proximal tibia metaphysis (PTM, by pQCT), 20% lower %BV/TV (nonsignificant) at the PTM, and 11% lower femoral neck maximal load; none of these HU-induced impacts were modified by E2. Impaired PTM periosteal expansion was observed in all E2-treated rats, with smaller (13 to 18%) cross-sectional areas. Midshaft tibial geometry was unaffected by E2 treatment, but large reductions (73 to 81%) in periosteal bone formation indices were observed in E2-treated rats.DISCUSSION: In summary, modest supplementation of exogenous E2 did not mitigate decrements in volumetric BMD, PTM cross-sectional geometry, or femoral neck strength observed with HU. However, numerous independent impacts of E2 treatment were observed, with significant suppression of periosteal bone formation indices. If maintained over time, this might impact negatively on cortical bone integrity during prolonged nonweightbearing.Mantri AV, Allaway HCM, Brezicha JE, Hogan HA, Bloomfield SA. Oral estradiol impact on mitigating unloading-induced bone loss in ovary-intact rats. Aerosp Med Hum Perform. 2021; 92(2):6574.

Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice

Objectives To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. Methods Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). Results Here, we show takinib’s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. Conclusion Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

Conditional disruption of miR17-92 cluster in collagen type I-producing osteoblasts results in reduced periosteal bone formation and bone anabolic response to exercise

In this study, we evaluated the role of the microRNA (miR)17-92 cluster in osteoblast lineage cells using a Cre-loxP approach in which Cre expression is driven by the entire regulatory region of the type I collagen α2 gene. Conditional knockout (cKO) mice showed a 13–34% reduction in total body bone mineral content and area with little or no change in bone mineral density (BMD) by DXA at 2, 4, and 8 wk in both sexes. Micro-CT analyses of the femur revealed an 8% reduction in length and 25–27% reduction in total volume at the diaphyseal and metaphyseal sites. Neither cortical nor trabecular volumetric BMD was different in the cKO mice. Bone strength (maximum load) was reduced by 10% with no change in bone toughness. Quantitative histomorphometric analyses revealed a 28% reduction in the periosteal bone formation rate and in the mineral apposition rate but with no change in the resorbing surface. Expression levels of periostin, Elk3, Runx2 genes that are targeted by miRs from the cluster were decreased by 25–30% in the bones of cKO mice. To determine the contribution of the miR17-92 cluster to the mechanical strain effect on periosteal bone formation, we subjected cKO and control mice to 2 wk of mechanical loading by four-point bending. We found that the periosteal bone response to mechanical strain was significantly reduced in the cKO mice. We conclude that the miR17-92 cluster expressed in type I collagen-producing cells is a key regulator of periosteal bone formation in mice.