ReviewTGF-β-related mechanisms of bone destruction in multiple myeloma
Section snippets
Myeloma cells enhance bone resorption and suppress bone formation
Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions. In typical destructive bone lesions of MM, osteoclastic bone resorption is enhanced with an impairment of bone formation. MM cells enhance osteoclastogenesis by a secretion of C–C chemokines, macrophage inflammatory protein (MIP)-1α and β [1], [2], [3]. As a result, MM creates a microenvironment rich in receptor activator of nuclear factor-kappaB ligand (RANKL), with deficient
Secretion of Wnt inhibitors by myeloma cells
In an effort to find out factors that suppress osteoblastic bone formation, Tian et al. [19] performed oligonucleotide microarray profiling and identified dickkopf1 (DKK1) as an inhibitor of OB differentiation secreted by MM cells. DKK1 is an inhibitor of canonical Wingless-type (Wnt) signaling pathway that has been shown to play an important role in OB differentiation. DKK1 binds to LDL-related protein 5 (LRP5), which serves as a coreceptor with Frizzled for Wnt and inhibits canonical Wnt
TGF-β suppresses bone formation
In addition to the Wnt inhibitors, there is another important inhibitor of OB differentiation and bone formation. Although many in vitro experiments demonstrated that transforming growth factor (TGF)-β enhances the recruitment and proliferation of OB progenitors and promotes matrix protein synthesis [23], TGF-β potently inhibits later phases of OB differentiation and maturation to suppress matrix mineralization [24], [25], [26]. Thus, TGF-β enhances the premature OB cell pool and matrix protein
TGF-β is deposited in bone matrix, released, and activated by bone resorption
TGF-β family consists of three isoforms, TGF-β1, -β2, and -β3 with high sequence homology. Among them, TGF-β1 is the most abundant isoform in bone, and bone contains about 200 μg/kg TGF-β1 [29], which is the second largest source to platelets in the body [30]. TGF-β1 is synthesized in OBs as a protein with three portions; the signal peptide with 29 amino acids, the latency-associated peptide (LAP) with 249 amino acids, and the mature peptide with 112 amino acids. The signal peptide is cleaved in
TGF-β signal is suppressed in malignant cells including myeloma cells
Although TGF-β inhibits proliferation of various cells, hematologic and other malignant cells including MM cells evade TGF-β signaling and maintain proliferation even in the presence of TGF-β. Various abnormalities in the constituents of TGF-β signaling pathway in malignant cells have been reported, including mutation, deletion, and disruption by oncoproteins of members of the TGF-β signaling pathway [35], [36]. TGF-β signal is transduced through type I and type II serine/threonine kinase
TGF-β inhibition enhances osteoblast differentiation
MM cells secrete Wnt inhibitors, sFRP-2 and 3 and DKK1, and enhance the release and activation of TGF-β from the bone matrix, both of which contribute to the suppression of OB differentiation and bone formation by MM. Therefore, enhancement of Wnt signaling or inhibition of TGF-β signaling may reverse the suppression of OB differentiation and bone formation. However, Wnt/β-catenin signaling is shown to be involved in cell cycle regulation, proliferation, and invasion of MM cells, contributing
Mature osteoblasts suppress myeloma cell growth and survival
Because MM cells suppress OB differentiation, immature OBs/stromal cells that support the survival and growth of MM cells surround MM cells. A recent report demonstrates that these mesenchymal stromal cells show distinct transcriptional profiles from OBs [52]. Thus, there was a question whether differentiation of mesenchymal stromal cells into mature OBs affects the growth/survival-promoting activity of stromal cells on MM cells. We examined MM cell growth and survival in cocultures with bone
Enhancement of osteoblast maturation by TGF-β inhibition suppresses myeloma growth
Because TGF-β inhibition reverses the suppression of terminal OB differentiation, and mature OBs suppress MM cell proliferation, there is a possibility that inhibition of TGF-β action in MM bone lesions may suppress MM cell growth. To examine such a possibility, an in vivo mice model was utilized in which an IL-6 or stromal cell-dependent human MM cell line, INA6, was inoculated directly into the bone marrow cavity of rabbit bones implanted subcutaneously to SCID mice (SCID-rab model) [54].
Conclusions
Suppression of OB differentiation plays an important role in the formation of devastating destructive lesions in the bone of MM patients. In addition to the bone lesions, because mature OBs inhibit the growth and survival of MM cells, the suppression of OB differentiation creates an environment suitable for MM growth. MM cells inhibit OB differentiation by secreting Wnt signal inhibitors, DKK1 and sFRP-2. However, Wnt signal enhances MM growth, and an approach to counteract Wnt inhibitors may
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