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 Runt-related transcription factor 2 (Runx2)/corebinding factor runt domain alpha subunit 1 (CBFA1) a transcription factor that is a part of the non-canonical WNT-signaling pathway myeloma cells decrease osteoblast differentiation by inhibiting RUNX2 activity in BMSCs and osteoblast precursor cells
EphrinB2/EphB4 signaling pathway Binding of ligands called ephrins (Eph receptor-interacting proteins) → activation of two cascades: 1) the forward signaling → ↑ osteoblast differentiation by downregulating RhoA; 2) the reverse signaling → ↓ osteoclast differentiation by ↓ Fos and Nfatc1 transcription EphrinB2 is found in osteoclasts EphB4 is found in osteoblasts and bone marrow stromal cells	Multiple myeloma patients have decreased expression of both EphrinB2 and EphB4 in bone marrow stromal cells.
Transforming growth factor-β (TGF-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	Inhibition of Transforming Growth Factor-β have been shown to prevent myeloma cells to block osteoblastic differentiation.
Bone morphogenetic proteins (BMPs) belong to TGFβ superfamily promote osteoblastogenesis through Smad-dependent and Smad-independent pathways	Myeloma cells express negative regulators of bone morphogenetic proteins that result in decreased activity of these proteins which in turn causes decreased osteoblastogenesis.
Hepatocyte growth factor (HGF) inhibits BMP-induced osteoblastogenesis, thought to be mediated by inhibition of nuclear translocation of receptor-activated SMADs	Produced by myeloma cells Increased levels have been shown to correlate with worse prognosis
Interleukin 3 (IL-3) inhibits BMP-induced osteoblastogenesis, thought to be mediated indirectly by increasing CD45+ hematopoietic cells	Elevated levels had been demonstrated in bone marrow of myeloma patients.
Interleukin 7 (IL-7) Causes increased osteoclastic activity decreased osteoblasts stimulation and maturation decreased Runx2/CBFA1 activity
Growth factor independence-1 (GFI1) a transcriptional repressor that causes decreased expression of RUNX2	Bone marrow stromal cells (BMSCs) in myeloma patients have been shown to over-express growth factor independence-1 (GFI1).
Tissue necrosis factor-α (TNF-α) inhibits osteoblast differentiation through inhibits osteoblast precursor recruitment suppresses RUNX2 and its transcriptional co-activator, TAZ	Tissue necrosis factor-α (TNF-α) levels are increased in multiple myeloma and it is thought to play a complex role in pathogenesis of multiple myeloma.
Adiponectin adipocyte-derived hormone thought to act on osteoblasts and osteoclasts	Increased adiponectin secretion through pharmacologic interventions have shown to decrease osteolytic lesions in myeloma.