Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies. PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines.Aims
Methods
Sclerostin is a negative regulator of osteoblast differentiation and bone formation. Expressed by osteocytes, it acts through antagonising the Wnt/â-catenin pathway and/or BMP activity. Distraction osteogenesis, used for limb lengthening and reconstruction, can be complicated by disuse osteopenia and poor healing response, both of which would benefit from pro anabolic therapy. We examined the effects of Sclerostin Antibody (Scl-AbIII, Amgen Inc.,) in a rat model of distraction osteogenesis. A femoral osteotomy was stabilized with an external fixator in male Sprague Dawley rats. After a week of latency, the gap was distracted twice daily for 14 days to a total of 7 mm. Saline or Scl-Ab was administered twice weekly throughout the distraction period and up to 4, 6 or 8 weeks post commencement of distraction. Three groups were examined: Saline, Continuous Scl-Ab throughout the study (C Scl-Ab), and Delayed Scl-Ab with commencement of Scl-Ab after distraction (D Scl-Ab). Regenerate bone mineral content (BMC), determined by DEXA, was increased 36% at 4 weeks and 86% at 6 weeks with C Scl-Ab, resulting in a 65% increase in bone mineral density (BMD) at 6 weeks, compared with Saline (p<0.01). D Scl-Ab treatment showed a 41% increase in BMC and a 31% increase in BMD compared with Saline at 6 weeks (p<0.05). At 8 weeks, C Scl-Ab remained significantly increased over Saline (72% in BMC; 60% in BMD). Micro-CT scans of the regenerate revealed increases in bone volume of 88% with C Scl Ab and 65% with D Scl-Ab compared with Saline at 6 weeks (p<0.05). By 8 weeks, these increases were 36% for C Scl-Ab (p<0.05) and 37% for D Scl-Ab compared with Saline (p<0.01). Importantly, mean moment of inertia was increased over two-fold in both Scl-Ab groups at 6 weeks compared with Saline (p<0.05). Histology at 6 weeks confirmed micro-CT data with 85–88% increases in bone volume/tissue volume (BV/TV) in the regenerate with both C Scl-Ab and D Scl-Ab compared with Saline (p<0.05). Analysis of bone formation at 6 weeks revealed increases in mineral apposition rate of 56% in C Scl-Ab and 52% in D Scl-Ab compared with Saline (p<0.05). Scl-Ab treatment increased bone formation in this model of distraction osteogenesis, resulting in a larger regenerate callus (increased BMC and BV/TV). We expect further studies to reveal increases in mechanical strength. Scl-Ab may hold promise as a therapeutic to accelerate regenerate formation and consolidation in distraction osteogenesis for limb reconstruction.
