Abstract
Myeloma bone disease (MBD), caused by the inhibition of osteoblast activity and the activation of osteoclast in the bone marrow environment, is the most frequent and life-threatening complication in multiple myeloma (MM) patients. Bortezomib (Bzb) was shown to promote MM-derived mesenchymal stem cells (MM-MSCs) differentiation to osteoblast in vitro and in animal models, promoting the bone formation and regeneration, may be mediated via β-catenin/T-cell factor (TCF) pathway. Further defining molecular mechanism of Bzb-enhanced bone formation in MM will be beneficial for the treatment of myeloma patients. The present study has identified for the first time four and a half LIM domains protein 2 (FHL2), a tissue-specific coregulator that interacts with many osteogenic marker molecules, as a therapeutic target to ameliorate MM bone disease. First, increased messenger RNA (mRNA) and protein levels of FHL2, and the mRNA level of main osteoblast markers (including Runx2, ALP, and Col1A1), were found in MM-patients-derived MSCs after Bzb treatment. FHL2 KD with short hairpin RNA (shRNA) reduced the expression of osteoblast marker genes and blocked the osteogenic differentiation of MM-MSCs regardless of the presence or absence of Bzb, implying that FHL2 is an important activator of the osteogenic differentiation of human MSCs under a proteasome inhibition condition. Molecular analysis showed that the enhanced expression of FHL2 was associated with the Bzb-induced upregulation of p53. No significant change at protein level of total β-catenin was observed with or without Bzb treatment. However, it was mostly enriched to nuclei in MSCs after Bzb treatment. Moreover, β-catenin was restricted to the perinuclear region in FHL2 KD cells. These data provide evidence that FHL2 is essential for promoting β-catenin nuclear enrichment in MM-MSCs. In conclusion, FHL2 is critical for Bzb-induced osteoblast differentiation of MM-MSCs and promotes the osteogenesis, through p53 signaling and β-catenin activation. Targeting FHL2 in MM may provide a new therapeutic strategy for treating MBD.
Highlights
Multiple myeloma (MM)-related bone disease (MBD), characterized by lytic bone lesions, fracture, hypercalcemia, and severe pain, is the most common and life-threatening complication in MM patients [1, 2]
Quantitative real-time PCR (RTPCR) analysis showed that messenger RNA levels of FHL2 and the main osteoblast markers Runx2, ALP, and Col1A1 were upregulated with 7 days treatment of Bzb at 2 nM (Figure 1D)
The present study has shown for the first time that FHL2, another important transcription factor, plays an critical role in the Bzb-induced osteoblast differentiation of MMMSCs and may represent a new target for the efficient promotion of bone regeneration
Summary
Multiple myeloma (MM)-related bone disease (MBD), characterized by lytic bone lesions, fracture, hypercalcemia, and severe pain, is the most common and life-threatening complication in MM patients [1, 2]. In addition to its anti-MM activity, preclinical and clinical data have shown that Bzb can inhibit osteoclast activity [7,8,9,10] and stimulate osteoblast activity [8,9,10,11,12,13,14], potentially exerting positive effects on bone metabolism [15, 16] independent of its effects on MM. Further defining molecular mechanism of Bzbenhanced bone formation in MM will be beneficial for the treatment of myeloma patients [5,6,7,8]
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