What is the role of Wnt signaling in the pathogenesis of osteoporosis?

Updated: Sep 26, 2019
  • Author: Monique Bethel, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

The Wnt family is a highly conserved group of proteins that were initially studied in relationship with cancer initiation and progression due to their involvement in intercellular communication. [24] Subsequently, the Wnt signaling cascade was recognized as a critical regulator of bone metabolism.

Wnt signaling plays a key role in the fate of mesenchymal stem cells (MSCs), which are the progenitor cells of mature bone-forming osteoblasts. [25] MSCs have the capability to differentiate into adipocytes, chondrocytes, neurons, and muscle cells, as well as into osteoblasts. [26] Certain Wnt signaling pathways promote the differentiation of MSCs along the osteoblast lineage. The emerging details about the specific molecules involved in the Wnt pathway have improved the understanding of bone metabolism and led to the development of new therapeutic targets for metabolic bone diseases.

Wnt signal activation may progress along one of three pathways, with the “canonical” pathway involving β-catenin being most relevant to bone metabolism. The canonical Wnt signaling pathway is initiated by the binding of a Wnt protein to an extracellular co-receptor complex consisting of “Frizzled” (Fr) and low density lipoprotein receptor–related protein–5 or –6 (LRP5, LRP6). [27] This activation recruits another protein, “Disheveled” (Dvl) to the intracellular segment of the Fz/Dvl co-receptor. [28] This is where β-catenin comes into play.

β-Catenin is an important intracellular signaling molecule and normally exists in a phosphorylated state targeted for ubiquination and subsequent degradation within intracellular lysosomes. Activation of the Wnt pathway leads to dephosphorylation and stabilization of intracellular β-catenin and rising cytosolic concentrations of β-catenin. As the concentration of β-catenin reaches a critical level, β-catenin travels to the nucleus, where it activates the transcription of Wnt target genes. Ultimately, canonical Wnt signaling inhibits the expression of transcription factors important in the differentiation of MSCs such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and promotes survival of osteoblast lineage cells. [29]

Several human bone abnormalities have been linked to the Wnt pathway. For example, a single amino acid substitution in the LRP5 receptor gene has been associated with high bone mass phenotypes in humans; specifically, the mutant LRP5 receptor had an impaired interaction with the Wnt signal inhibitor Dickkopf-1 (Dkk-1). [30] Similarly, other missense mutations of LRP5 have been implicated in other high bone mass diseases such as Van Buchem disease and osteopetrosis. [31] Conversely, loss-of-function mutations of LRP5 have resulted in a rare but severe congenital osteoporosis in humans. [32]

There are also several antagonists to the Wnt pathway. Two of the most well-known are Dkk-1 and sclerostin. Dkk-1 is secreted by MSCs [33] and binds to LRP-5 and LRP-6, [34] thereby competitively inhibiting Wnt signaling. Interestingly, serum levels of Dkk-1 positively correlate with the extent of lytic bone lesions in patients with multiple myeloma. [35]  In animal models, anti-Dkk1 monoclonal antibody accelerates bone formation and increases bone mineral density, and anti-Dkk antibody is under development as a bone-anabolic agent. [36]

Similarly, sclerostin, a product of osteocytes, [37] has also been found to antagonize the Wnt signaling pathway by binding to LRP5 and LRP6. [38] Romosozumab, a monoclonal antibody that binds with and inhibits sclerostin, and thus both increases bone formation and decreases bone resorption, has been approved for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. [39]


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