Wnt/b-catenin Pathway

This pathway plays an important role in the main processes controlling osteogenesis.
Regulates gene transcription of proteins important for osteoclast formation.
Experiments show that activation of Wnt/b-catenin pathway induces cellular replication and  differentiation of osteoblasts, reducing adipogenic differentiation MSCs.

COMPONENTS OF Wnt/B-CATENIN PATHWAY:
Composed of Wnt proteins, frizzled transmembrane receptors and low density lipoprotein receptor-related protein 5/6 (LRP 5/6).

Wnt signaling is activated by the presence of Wnt ligand, which interacts with its receptor, thereby inhibiting the receptor. This interaction leads to cytoplasmic accumulation of b-catenin, which translocates to the nucleus, activating a fundamental transcription factor, RUNX-2, involved in osteogenic differentiation.
However, in the absence of Wnt ligand, b-catenin is phosphorylated by glycogen synthase kinase 3 beta (GSK3B) leading to its degradation, leading to a halt in gene transcription.

Studies show that use of GSK3B in aged and osteopenic mice, the Wnt signaling cascade enhance bone formation and increased bone strength *****(include this if you want)

Other inhibitors of the Wnt signaling pathway secreted by osteoclasts are:
SOST protein
DKK 1 protein

Both are Wnt antagonists specific to bone. Bincreadsoth block binding of Wnt to LRP5 and therefore inhibit osteoblast stimulation.

Studies show loss of function mutation of SOST leads to increase in bone formation and mass. Many forms of cancer are associated with this mutation.

Currently monoclonal antibodies designed to block inhibitory action of both SOST and DDK 1 has been introduced for use in clinical trials

The development of pharmacological SOST and DDK 1 antagonists that increase bone formation and bone mass in a new strategy in treatment of bone disorders.

Animal studies show that systemic administration of an anti-SOST MAB increased bone formation, bone mass and bone strength.

Also: anti-SOST antibody was able to enhance bone formation in post menopausal women.
Pre-clinical studies on administration of SOST neutralizing monoclonal antibodies show:
Increased bone formation without bone resorption

summary

Prevention and treatment of several bone diseases are possible.

 Due to development of a variety of drugs that act to halt excessive bone resorption by inhibiting osteoclasts or by promoting bone formation.

BP: alendronate and zoledronic acid

Significantly reduce risk of vertebral, non-vertebral and femoral fractures by decreasing bonefemoral fractures remodeling via inhibition of osteoclasts with increased bone mass.

Long term use correlated with occurrence of atypical fractures.

New approach: targets the inhibition of osteoclast activity inhibits RANK1. 

RANKL: involved in survival and differentiation of mature osteoclasts.

RANKL inhibitor: denosumab

Exerts inhibitory action on osteoclastogenesis.

Studies of histomorphometry: PTH1 34 was able to increase trabecular bone mass in post-menopausal women 

Raloxifene: modulates homeostasis of bone cells in vitro by inhibiting osteoclastogenesis and bone resorption. Reduces overall number of preosteoclasts and mature osteoclasts