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Human scaphoid non-unions exhibit increased osteoclast activity compared to adjacent cancellous bone.

ABSTRACT: Scaphoid bones have a high prevalence for non-union. Even with adequate treatment, bone regeneration may not occur in certain instances. Although this condition is well described, the molecular pathology of scaphoid non-unions is still poorly defined. In this study, gene expression of osteogenic and angiogenic growth and transcription factors as well as inflammatory mediators were analysed in human scaphoid non-unions and intraindividually compared to adjacent autologous cancellous bone from the distal radius. In addition, histology and immunohistochemical stainings were performed to verify qRT-PCR data. Gene expression analysis revealed a significant up-regulation of RANKL, ALP, CYCLIN D1, MMP-13, OPG, NFATc1, TGF-β and WNT5A in scaphoid non-unions. Interestingly, RANKL and NFATc1, both markers for osteoclastogenesis, were significantly induced in non-unions. Moreover, WNT5A was highly up-regulated in all non-union samples. TRAP staining confirmed the observation of induced osteoclastogenesis in non-unions. With respect to genes related to osteogenesis, alkaline phosphatase was significantly up-regulated in scaphoid non-unions. No differences were detectable for other osteogenic genes such as RUNX-2 or BMP-2. Importantly, we did not detect differences in angiogenesis between scaphoid non-unions and controls in both gene expression and immunohistochemistry. Summarized, our data indicate increased osteoclast activity in scaphoid non-unions possibly as a result of the alterations in RANKL, TGF-β and WNT5A expression levels. These data increase our understanding for the reduced bone regeneration capacity present in scaphoid non-unions and may translate into the identification of new therapeutic targets to avoid secondary damages and prevent occurrence of non-unions to scaphoid bones.

SUBMITTER: Schira J

PROVIDER: S-EPMC4687713 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundDelayed fracture healing continues to cause significant patient morbidity and an economic burden to society. Biological stimulation of non-unions includes application of recombinant bone morphogenetic protein-2 (rhBMP-2). However, rhBMP-2 use continues to be a matter of controversy as literature shows scarce evidence for treatment effectiveness.QuestionsThe objective of this study was to evaluate the effectiveness of rhBMP-2 treatment on long bone non-unions measuring union rate and time to union. Furthermore, we assess risk factors for treatment failure.Methods and patientsA total of 91 patients with non-unions of long bones were treated with rhBMP-2 (n = 72) or standard care without BMP (n = 19) at our institution. Patient characteristics, comorbidities, nicotine consumption, and complications were recorded. Bone healing was assessed by plane X-rays and clinical examination. Patients were followed up with for 24 months.ResultsOverall, there was significantly faster bone healing after rhBMP-2 application compared to the no-BMP group (p < 0.001; HR = 2.78; 95% CI 1.4-5.6). Union rates differed significantly between rhBMP-2 compared to the no-BMP group (89% vs. 47%; p < 0.001). At the humerus, there was neither a significantly higher union rate in the rhBMP-2 (83%) compared to the no-BMP group (50%) (p = 0.26; n = 12) nor a faster bone healing with a median time of 9 months in both groups (HR = 2.01; 95% CI 0.49-8.61; p = 0.315). The 33 femora treated using rhBMP-2 healed significantly faster than 9 femora in the no-BMP group (HR = 2.93; 95% CI 1.00-8.4; p = 0.023) with significant differences in union rate with 85% and 44%, respectively (p = 0.022). Regarding tibia non-unions, 25 out of 27 (93%) healed with a median of 9 months after rhBMP-2 application with no significant difference in the no-BMP group (33%) in time to union (p = 0.097) but a significantly higher union rate (p = 0.039). There was no effect of comorbidities, age, sex, soft tissue damage, or nicotine use on time to union, union rate, or secondary interventions.ConclusionConsistent with the literature, overall, significantly higher union rates with reduced time to union were achieved after rhBMP-2 application. Femoral and tibial non-unions in particular seem to profit from rhBMP-2 application.

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Human scaphoid non-unions exhibit increased osteoclast activity compared to adjacent cancellous bone.

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