In Vivo Analysis of Wnt Signaling in Bone

ArticleinEndocrinology 148(6):2630-4 · June 2007with3 Reads
Impact Factor: 4.50 · DOI: 10.1210/en.2006-1372 · Source: PubMed

Bone remodeling requires osteoblasts and osteoclasts working in concert to maintain a constant bone mass. The dysregulation of signaling pathways that affect osteoblast or osteoclast differentiation or function leads to either osteopenia or high bone mass. The discovery that activating and inactivating mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, led to high bone mass and low bone mass in human beings, respectively, generated a tremendous amount of interest in the possible role of the Wnt signaling pathway in the regulation of bone remodeling. A number of mouse models have been generated to study a collection of Wnt signaling molecules that have been identified as regulators of bone mass. These mouse models help establish the canonical Wnt signaling pathway as a major regulator of chondrogenesis, osteoblastogenesis, and osteoclastogenesis. This review will summarize these advances.

    • "During new bone layer formation, osteoblasts differentiate into terminal stage osteocytes. The canonical Wnt signaling pathway plays a crucial role in normal bone development [21,858687888990919293949596 in the regulation of both osteoblasts and osteoclasts (Figure 2). In osteoblasts, Wnt signaling influences three major developmental functions: the commitment of MSCs to an osteoblast stem cell type; stimulation of osteoblast proliferation; and promotion of osteoblast and osteocyte survival [92,979899. "
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    • "Bone anabolic stimuli activate this pathway and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive, as activation of Wnt/β-catenin signaling in preosteoblasts or osteoblasts inhibits resorption without increasing bone forma- tion[33]. This new evidence now showed that, in contrast, activation of canonical Wnt signaling in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival[32•]. "
    [Show abstract] [Hide abstract] ABSTRACT: For many years osteocytes have been the forgotten bone cells and considered as inactive spectators buried in the bone matrix. We now know that osteocytes detect and respond to mechanical and hormonal stimuli to coordinate bone resorption and bone formation. Osteocytes are currently considered a major source of molecules that regulate the activity of osteoclasts and osteoblasts, such as RANKL and sclerostin, and genetic and pharmacological manipulations of either molecule markedly affect bone homeostasis. Besides playing a role in physiological bone homeostasis, accumulating evidence supports the notion that dysregulation of osteocyte function and alteration of osteocyte lifespan underlies the pathophysiology of skeletal disorders characterized by loss bone mass and increased bone fragility, as well as the damaging effects of cancer in bone. In this review, we highlight some of these investigations and discuss novel observations that demonstrate that osteocytes, far from being passive cells entombed in the bone, are critical for bone function and maintenance.
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    • "Genome-wide experiments revealed that most of the pathways (e.g. TGFβ/BMP, WNT and ERK/MAPK pathways) are involved, and may putatively cross-talk, during transcriptional regulation of osteoblast differentiation, proliferation and maturation5455565758. Our results suggest that the pathways involved in the regulation of osteoblast differentiation and proliferation are down-regulated in deformed fish. "
    [Show abstract] [Hide abstract] ABSTRACT: The prevalence of bone deformities, particularly linked with mineral deficiency, is an important issue for fish production. Juvenile triploid rainbow trout (Oncorhynchus mykiss) were fed a low-phosphorus (P) diet for 27 weeks (60 to 630 g body mass). At study termination, 24.9% of the fish fed the low-P diet displayed homogeneous biconcave vertebrae (deformed vertebrae phenotype), while 5.5% displayed normal vertebral phenotypes for the entire experiment. The aim of our study was to characterize the deformed phenotype and identify the putative genes involved in the appearance of P deficiency-induced deformities. Both P status and biomechanical measurements showed that deformed vertebrae were significantly less mineralized (55.0 ± 0.4 and 59.4 ± 0.5, % ash DM, for deformed and normal vertebrae, respectively) resulting in a lower stiffness (80.3 ± 9.0 and 140.2 ± 6.3 N/mm, for deformed and normal phenotypes, respectively). The bone profiles based on μCT observations showed no difference in the osteoclastic resorption while no difference in matrix production was observed between deformed (total bone area 5442.0 ± 110.1 μm2) and normal vertebrae (total bone area 5931.2 ± 249.8 μm2) in this study. Consequently, the lower P content rather results from a reduced degree of mineralization in the deformed phenotype. Finally, we quantified differential gene expression between deformed vertebrae (pronounced biconcave) and normal phenotype by employing deep RNA-sequencing and mapping against a reference bone transcriptome for rainbow trout. In total, 1289 genes were differentially expressed. Among them, in deformed fish we observed that BGLAP, MGP and NOG, an inhibitor of BMP signalling pathway, were up-regulated while COL11a1 was down-regulated. These genes are central actors involved in the reduced degree of mineralization triggering vertebral deformities. These results will further the understanding of P deficiency-induced deformities; hence providing new tools for improved P management in production settings
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