M. Hooper

Long-Term Control of Bone Turnover in Paget's Disease With Zoledronic Acid and Risedronate

A single 5‐mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Pagets disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy.

Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: Evidence for a founder effect in patients of British descent

Mutations in the UBA domain of SQSTM1 are a common cause of Pagets disease of bone. Here we show that the most common disease‐causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin.

Genome wide association study identifies seven loci that account for 86% of the population attributable risk of Paget's disease of bone

Objectives: Recently, we have identified DLKl/FA1 (delta like 1/fetal antigen1) as a novel marker of chondroprogenitor cells that undergo embryonic lineage progression from proliferation to the prehypertrophic stage (Harkness L, et al., Stem Cell Rev and Rep, 2009;5:353). We aimed in this study to investigate the regulatory role of Dlk1/FA1 in chondrogenesis. Materials/Methods: We used the mouse embryonic limb mesenchymal micromass culture as an in vitro system that recapitulates the sequential stages of chondrogenesis. In this culture system, we examined the possible regulation of DLK1/ FA1 expression in response to different signal pathways and their antagonists that involved in the entire program of cartilage development. Real-time PCR, immunostaining and ELISA (for active soluble form of DLK1/FA1) assays were used. Results: Our data showed that DLK1/FA1 started to be expressed at stages of mesenchyme condensation (day 1–3) and peaked up through chondrogenesis (day 3–6) in parallel with the expression of Sox9 and type II collagen, while dramatically down-regulated after day 7 to be abolished completely upon the expression of ColX by hypertrophic chondrocyte at day 10. Interestingly, TGF-β1 (an early signal for condensation/differentiation) treatment delays chondrocyte hypertrophy and inhibits matrix mineralization in parallel with marked down-regulation of Dlk1 expression (by 80%) without affecting the expression of early chondrogenic markers Sox9 and Col2a1. In contrast, blocking of TGF-β1 signal using SB431542 strongly inhibits mesenchyme condensation and chondrogenesis in parallel with marked stimulation ofDlk1 expression (by 4-fold), suggesting an involvement of DLK1/FA1 in mediating the function of TGF-β1 signalling in chondrogenesis. In support of this hypothesis, we found that TGF-β1 enhanced chondrocyte differentiation in Dlk1MEF compared to wild type MEF. Conclusions: In conclusion, our data identified TGF-β1 as an upstream negative regulator of Dlk1 expression and function during the early events of embryonic chondrogenesis. The cross-talk between TGF-β1 and DLK1 showed to promote early chondrogenesis during embryonic endochondral bone formation process. Disclosure of Interest: None declared.