Update on Wnt signaling in bone cell biology and bone disease

Abstract

For more than a decade, Wnt signaling pathways have been the focus of intense research activity in bone biology laboratories because of their importance in skeletal development, bone mass maintenance, and therapeutic potential for regenerative medicine. It is evident that even subtle alterations in the intensity, amplitude, location, and duration of Wnt signaling pathways affects skeletal development, as well as bone remodeling, regeneration, and repair during a lifespan. Here we review recent advances and discrepancies in how Wnt/Lrp5 signaling regulates osteoblasts and osteocytes, introduce new players in Wnt signaling pathways that have important roles in bone development, discuss emerging areas such as the role of Wnt signaling in osteoclastogenesis, and summarize progress made in translating basic studies to clinical therapeutics and diagnostics centered around inhibiting Wnt pathway antagonists, such as sclerostin, Dkk1 and Sfrp1. Emphasis is placed on the plethora of genetic studies in mouse models and genome wide association studies that reveal the requirement for and crucial roles of Wnt pathway components during skeletal development and disease.

Fig. 1

Wnt signaling pathways. The “canonical” Wnt–β-catenin signaling pathway is illustrated in the center of the diagram. Secreted and intracellular inhibitors of β-catenin are shown on the right side. Wnt signaling pathways that do not involve β-catenin are summarized on the left side.

Fig. 2

Cell lineages involved in bone development and homeostasis. Osteoblasts and chondrocytes are derived from mesenchymal progenitor cells, whereas osteoclasts are derived from hematopoietic precursors. Various promoters (indicated at the top and bottom of the diagram in gray boxes) drive transgene or Cre expression in these cells at various stages of their maturation. Mature osteoblasts and osteocytes stimulate osteoclast maturation through Rankl–Rank interactions, but also secrete the decoy receptor Opg to regulate the process. Osteocytes secrete Scl to inhibit Lrp5 activities. PTH and mechanical loading suppress Scl production by osteocytes to increase bone formation.