The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.
This finding suggests that the production and/or activity of sclerostin can be titrated in vivo, leading to variable increases in bone mass without any unwanted skeletal effects, a hypothesis of obvious significance for the development of new therapeutics for osteoporosis.
This finding suggests that the production and/or activity of sclerostin can be titrated in vivo, leading to variable increases in bone mass without any unwanted skeletal effects, a hypothesis of obvious significance for the development of new therapeutics for osteoporosis.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
We sought to determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis/bone mineral density (BMD) variation in the normal Chinese population.
We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.
Among the most distinctly expressed genes were Wnt antagonists DKK1 and SOST, the transcription factor SOX4, and the bone matrix proteins MMP13 and MEPE, all reduced in osteoporosis versus control groups.
This observation has led to the concept that compounds that reduce sclerostin levels might mimic the heterozygous carrier state and be effective in the treatment of osteoporosis.
In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2.
Sirt1 activation by Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions.
The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively).
In conclusion, by showing a direct correlation between T and sclerostin, both in vivo and in vitro, this study adds further support to the emerging clinical and experimental studies focusing on sclerostin as a therapeutic target for osteoporosis treatment.
Identification of the disease causing genes, increased the knowledge on the regulation of BMD and highlighted important signaling pathways and novel therapeutic targets such as sclerostin, RANKL and cathepsin K. Genetic variation in genes involved in these pathways are often also involved in the regulation of normal variation in BMD and osteoporosis susceptibility.
Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice.
The most promising new drugs in the treatment of osteoporosis include the antibody that neutralizes RANKL (denosumab, DMAb), monoclonal antibodies against sclerostin and parathyroid hormone-related protein analogue.
There was a positive, high-level relationship between sclerostin levels and BMI in the osteoporosis group and it was found to be statistically significant (p < 0.001, r = 0.786).
Romosozumab, a humanized monoclonal sclerostin antibody under development for the treatment of osteoporosis, has a unique mechanism of action on bone-increasing bone formation and decreasing bone resorption.