Wnts’ fashion statement: from body stature to dysplasia

Abstract

Bone is constantly being made and remodeled to maintain bone volume and calcium homeostasis. Even small changes in the dosage, location and duration of int/Wingless (Wnt) signaling affect skeletal development and homeostasis. Wnt/b-catenin signaling controls cell fate determination, proliferation and survival by affecting a balance between boneforming osteoblast and bone-resorbing osteoclast cell differentiation. During early skeletal development, Wnt/b-catenin signaling is required in directing mesenchymal progenitor cells toward the osteoblast lineage. Later, Wnt/b-catenin in chondrocytes of the growth plate promotes chondrocyte survival, hypertrophic differentiation and endochondral ossification. Gain-or loss-of-function mutations in the Wnt signaling components are causally linked to high or low bone mass in mice and humans. Inactivation of Wnt/b-catenin signaling leads to imbalance between bone formation and resorption because of accelerated osteoclastogenesis due to decline in the levels of osteoprotegerin (OPG) secreted by osteoblasts or directly via Frizzled 8 (Fzd8). In this review, we provide a landscape of the Wnt pathway components in influencing progenitor cell differentiation toward osteoblasts or osteoclasts under physiological conditions as well as pathological disorders resulting in various skeletal dysplasia syndromes.

Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects

“…The postnatal chondrocyte differentiation and bone elongation are under tight control by multiple signaling pathways that form a signaling balance between the growth plates and periarticular cartilage, such as those directed by WNTs, bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Indian hedgehog (IHH), and parathyroid hormone-related peptide (PTHrP), which are required for the proliferation and differentiation of chondrocytes 2 3 . During chondrocyte differentiation, WNT signaling is generally believed to promote chondrocyte hypertrophy and final maturation 4 5 , BMPs induce chondrocyte proliferation and maturation 6 , while PTHrP and IHH are known to mediate chondrocyte hypertrophy by forming a negative feedback loop 7 .…”

Altered heparan sulfate structure in Glce−/− mice leads to increased Hedgehog signaling in endochondral bones

“…In this context it is interesting to note that many mouse lines deficient for GAG-synthesizing enzymes show very particular defects in different organs, while the ossification process, though not described in much detail, seems to be only mildly affected (17,24,25). This is especially surprising as many signaling pathways affected by an altered HS structure in other organs also regulate chondrocyte differentiation, as for example Fgf, Bmp and Wnt signaling (4,26). Chondrocytes might thus be less sensitive to modulation of the HS pattern.…”

Establishment of a porcine pancreatic stem cell line using T‐REx™ system‐inducible Wnt3a expression

“…The Wnt signalling pathway involves a large number of proteins that are required for basic developmental processes, such as cell fate specification, progenitor cell proliferation and control of asymmetric cell division, in many different organs and species . Previous studies have produced evidence that pancreatic growth and pancreatic cell differentiation are regulated by Wnt signalling .…”