Sandbox:Hannan

Molecular pathways and factors associated with osteoblastic activity	Association with multiple myeloma
Wingless and integration-1 (Wnt) signaling Canonical pathway Activation of Wnt pathway → binding of Wnt ligands to Wnt co-receptors LRP5/6 and one trans-membrane receptor of the FDZ family → formation of DVL–Axin–FRAT1–GSK-3β complex → translocation of β-catenin from cytoplasm to nucleus → activation of T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors → ↑ bone formation and ↓ bone resorption Non-canonical WNT–planar cell polarity (WNT–PCP) pathway Formation of WNT ligand–receptor tyrosine kinase-like orphan receptor 2 (ROR2) or the receptor-like tyrosine kinase (RYK)–FZD–DVL complex → activation of one of these 3 pathways: 1) Disheveled-associated activator of morphogenesis 1 (DAAM1)–RHO–RHO-associated kinase (ROCK) pathway; 2) RAC–Jun kinase (JNK)–RUNX2 pathway; WNT–Ca2+ pathway Binding of PTH to PTH1 receptor may result in activation of Wnt pathway This pathway is also involved in cell-cycle promotion and cell growth	Dickkopf 1 (Dkk-1) an extracellular inhibitor of this pathway expressed by osteoblasts and bone marrow stromal cells, is thought to play the crucial role in osteoblastic inhibition in multiple myeloma. The serum levels and the expression of Dickkopf 1 (Dkk-1) by bone marrow cells were found to increased in patients with multiple myeloma. Sclerostin secreted by osteocytes, sclerostin is a cysteine knot-containing protein activates the caspase pathway, resulting in apoptosis of mature osteoblasts binds to LRP5/6 transmembrane receptors preventing the Wnt ligand- LRP5/6 transmembrane receptors binding, that leads to inhibition of Wnt signaling pathway promotes osteoclastogenesis by increasing RANKL/OPG ratio elevated levels have been found in all phases of multiple myeloma and is considered to be a worse prognosis factor. Furthermore, myeloma cells have been shown to secrete sclerostin Secreted frizzled related protein-2 (sFRP-2) prevents binding of Wnt ligands to frizzled, a membrane bound receptor some studies suggest that myeloma cells express sFRP-2 that antagonizes bone formation Periostin produced by bone marrow stromal cells, periostin is an adhesion protein of fasciclin family thought to activate the integrin–AKT–FAK–β-catenin pathway although the role is still unclear, elevated levels have been found in almost all the patients presenting with multiple myeloma
Transforming Growth Factor-β a ubiquitous, multifunctional growth factor produced by osteocytes and osteoblasts and is activated by osteoclasts primary effect in bone marrow is the inhibition of terminal differentiation of osteoblasts