Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

The skeleton as an organ is widely distributed throughout the entire vertebrate body. Wnt signaling has emerged to play major roles in almost all aspects of skeletal development and homeostasis. Because abnormal Wnt signaling causes various human skeletal diseases, Wnt signaling has become a focal point of intensive studies in skeletal development and disease. As a result, promising effective therapeutic agents for bone diseases are being developed by targeting the Wnt signaling pathway. Understanding the functional mechanisms of Wnt signaling in skeletal biology and diseases highlights how basic and clinical studies can stimulate each other to push a quick and productive advancement of the entire field. Here we review the current understanding of Wnt signaling in critical aspects of skeletal biology such as bone development, remodeling, mechanotransduction, and fracture healing. We took special efforts to place fundamentally important discoveries in the context of human skeletal diseases.The skeleton has many important functions related to human health. Aside from the classical functions of the skeleton in structural support and movement, the bone matrix forms a major reservoir of calcium and other inorganic ions, and bone cells are active regulators of calcium homeostasis. Recent data suggest that bone cells can secrete hormones (e.g., FGF23 and osteocalcin) and likely play a physiologically significant role in regulating phosphate and energy homeostasis. It has emerged that Wnt signaling plays a major role controlling multiple aspects of skeletal development and maintenance. Thus, understanding how the Wnt pathway controls skeletal growth and homeostasis has broad implications for human health and disease.Cartilage and bone define the skeleton and are produced by chondrocytes and osteoblasts, respectively. During embryonic development, bones are formed by two distinct processes: intramembranous and endochondral ossification (Fig. 1A). A number of cranial bones and the lateral portion of the clavicles are formed by intramembranous ossification. In this process, mesenchymal progenitor cells condense and differentiate directly into bone-forming osteoblasts. The majority of bones in our body are formed by endochondral ossification, during which mesenchymal progenitor cells condense and differentiate first into cartilage-forming chondrocytes to generate an avascular template of the future bone. Chondrocytes in these templates undergo a program of proliferation and progressive cellular maturation. Eventually, they exit the cell cycle and become pre-hypertrophic, then terminally differentiating into hypertrophic chondrocytes, which are eliminated ultimately by apoptosis. Hypertrophic chondrocytes produce a matrix that is calcified and functions as a scaffold for new bone formation. Concomitant with chondrocyte hypertrophy, osteoclasts, osteoblasts, and blood vessels migrate in from perichondral regions and remodel this template into bone.Open in a separate windowFigure 1.Mechanisms of skeleton formation. (A) Bones can form by either intramembranous or endochondral ossification. Both processes are initiated by the condensation of mesenchymal cells. During intramembranous ossification, mesenchymal cells differentiate directly into osteoblasts and deposit bone. During endochondral ossification, mesenchymal cells differentiate into chondrocytes and first make a cartilage intermediate. Chondrocytes in the center of the bone initiate a growth plate, stop proliferating, and undergo hypertrophy. Hypertrophic chondrocytes mineralize their matrix and undergo apoptosis, attracting blood vessels and osteoblasts that remodel the intermediate into bone. (B) The first histologic sign of synovial joint formation is the gathering and flattening of cells, forming the interzone. Cavitation occurs within the presumptive joint separating the two cartilaginous structures. Remodeling and maturation proceed to give rise to the mature synovial joint. Wnt signaling plays a significant role in controlling almost all aspects of skeleton formation. Osteoblasts (purple); chondrocytes (blue); osteochondroprogenitor cells (brown).The developing skeletal elements are often segmented to form joints, which are required to support mobility. Synovial joints, which allow movement via smooth articulation between bones, form when chondrogenic cells in a newly formed cartilage undergo a program of dedifferentiation and flattening to form an interzone (Fig. 1B). Cavitation occurs within the flattened cells, allowing physical separation of the skeletal elements, and the formation of the synovial cavity. Cells and tissues in and around the interzone are remodeled at the same time to form the articular cartilage and other joint structures. Failure to form or maintain joints leads to joint fusion or osteoarthritis, a major skeletal disease.Following its formation, bone remains a regenerative tissue and is maintained during postnatal life by continuous remodeling. This highly active, homeostatic process is required for its functions and is controlled by three cell types: osteoblasts on the bone surface that deposit new bone matrix; osteocytes embedded in bone that are terminally differentiated from osteoblasts and function as mechanical and metabolic sensors; and the matrix-resorbing osteoclasts (Fig. 2). Osteoblasts are derived from mesenchymal stem cells (MSCs), whereas osteoclasts differentiate from hematopoietic progenitors. Decreased bone mass may be due to reduced osteoblast function or elevated osteoclast activity, and, conversely, increased bone mass may result from increased osteoblast function or decreased osteoclast activity. The precise balance of formation and resorption is critical for maintaining normal bone mass, and alterations in this balance lead to common bone diseases such as osteoporosis and osteopetrosis.Open in a separate windowFigure 2.Anatomy of bone. Cortical and trabecular bone represent the two major forms of bone. Osteoblasts (dark purple) are present on the surface and form new bone. Osteocytes (brown) are terminally differentiated osteoblasts that have become embedded in bone and communicate information to one another and to cells on the surface to regulate bone homeostasis. Osteoclasts (blue) are of hematopoietic origin and catabolize bone. A major function of Wnt/β-catenin signaling in osteoblasts is to suppress RANKL and to promote OPG production, thereby inhibiting osteoclast formation.There are two major bone types, cortical and trabecular, which show different anatomical properties (Fig. 2). Cortical (or compact) bone is the solid, densely packed bone that forms the outer layer of most bones and gives strength and rigidity. Trabecular (or cancellous) bone is present mostly in the marrow cavities of long bones and is the dominant bone type in vertebral bodies. Trabecular bone forms a porous, cobweb-like network of trabeculae whose large surface area is thought to facilitate the metabolic activity of bones mediated by osteoblasts and osteoclasts. Trabeculae are sites of active remodeling and will often orient in the direction of mechanical loading, dissipating the energy of loading and adding to bone strength. It is trabecular bone, rather than cortical bone, which is most severely affected in osteoporosis.The Wnt/β-catenin pathway plays a major role in controlling skeletal development and homeostasis, which are the focus of this work. We focus not only on differentiation of skeletal cells and formation of skeletal tissues, but also on the role of the Wnt/β-catenin signaling pathway on bone homeostasis, mechanotransduction, and wound healing, paying particular attention to human and mouse studies.