9 research outputs found
Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease
BACKGROUND
Cortical-bone fragility is a common feature in osteoporosis that is linked to non
-
vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The
study of genetic disorders of the skeleton can yield insights that fuel experimental
therapeutic approaches to the treatment of rare disorders and common skeletal
ailments.
METHODS
We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized
by cortical-bone thinning, limb deformity, and fractures; two patients were examined
by means of exome sequencing, and two were examined by means of Sanger se
-
quencing. After a candidate gene was identified, we generated a knockout mouse
model that manifested the phenotype and studied the mechanisms responsible for
altered bone architecture.
RESULTS
In all affected patients, we found biallelic truncating mutations in
SFR P4
, the gene
encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient
in
Sfrp4
, like persons with Pyle’s disease, have increased amounts of trabecular bone
and unusually thin cortical bone, as a result of differential regulation of Wnt and
bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat
-
ment of
Sfrp4-
deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti
-
bodies to sclerostin corrected the cortical-bone defect.
CONCLUSIONS
Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical-
bone and trabecular-bone homeostasis were governed by different mechanisms, and
that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical
for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na
-
tional Foundation and the National Institutes of Health.
Recommended from our members
Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma
Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority. We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is a novel antagonist of Activin receptor-like kinase 1 (ALK1)/Bone morphogenetic protein (BMP) 9 signaling. Dalantercept inhibited growth in the murine A498 xenograft model which correlated with hyperdilation of the tumor vasculature and an increase in tumor hypoxia. When combined with sunitinib, dalantercept induced tumor necrosis and prevented tumor regrowth and revascularization typically seen with sunitinib monotherapy in two RCC models. Combination therapy led to significant downregulation of angiogenic genes as well as downregulation of endothelial specific gene expression particularly of the Notch signaling pathway. We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as ALK1 and VEGFR, is a valid strategy for treatment of mRCC. At the molecular level, combination therapy leads to downregulation of Notch signaling
COMMD5/HCaRG Hooks Endosomes on Cytoskeleton and Coordinates EGFR Trafficking
Summary: COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity. : COMMD5/HCaRG is involved in endocytic trafficking. Campion et al. describe the link between COMMD5, the cytoskeletal proteins actin and tubulin, and Rab5-associated endosomes in epithelial cells. COMMD5 directly interacts with actin and tubulin at one end and Rab5 at the other end to drive membrane proteins across endosomal compartments and thereby regulate EGFR trafficking and activation and directional cell migration. Keywords: COMMD5/HCaRG, endosome trafficking, early and recycling endosomes, Rab, receptor trafficking, EGFR, tubulin, microtubule, actin, migratio