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Evidence for the dysregulated expression of TWIST1, TGFβ1 and SMAD3 in differentiating osteoblasts from primary hip
D D Kumarasinghe1, T Sullivan, J S Kuliwaba
1Bone Cell Biology Group, Discipline of Orthopaedics & Trauma, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Objective:
This study compared human primary osteoblasts derived from hip osteoarthritis (OA) cases against controls (CTLs) to investigate candidate OA disease genes, twist homologue 1 (TWIST1), wingless MMTV integration site family member 5B (WNT5B), transforming growth factor-β (TGFβ1) and SMAD family member 3 (SMAD3), during osteoblast differentiation, relative to calcium apposition and elemental mineral composition.
Materials & Methods:
Primary osteoblast cultures were generated from intertrochanteric trabecular bone samples from five female primary hip OA cases and five age-matched female CTLs. During a 42-day differentiation time-course, alizarin red stains, energy-dispersive X-ray spectroscopy and real-time RT-polymerase chain reaction (PCR) were used to quantify calcium, elemental composition and gene expression, respectively. Data were analysed using linear mixed effects models and Pearson correlation matrices.
Results:
Significant differences, correlations and associations were found in OA and CTL osteoblasts between gene and mineral measures. The calcium: phosphorous (Ca:P) ratio was significantly more varied in OA compared to CTL. Calcium apposition, mineral composition as well as TWIST1 and TGFβ1 mRNA expression changed significantly over time. TWIST1 mRNA expression was elevated and correlated with SMAD3 mRNA levels in the OA cohort during the time-course. Associations were observed between tissue non-specific alkaline phosphatase (TNAP), osteocalcin (OCN), TWIST1, TGFβ1, SMAD3 mRNA levels and mineral measures in OA against CTL. Temporal differences between SMAD3 mRNA expression and mineral composition were also found in OA.
Conclusions:
Dysregulated expression of TWIST1, TGFβ1 and SMAD3 mRNA observed in OA bone is reflected in the functionality of the osteoblast when these cells are cultured ex vivo. The results presented here are consistent with at least part of the aetiology of primary hip OA deriving from altered intrinsic properties of the osteoblast.
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