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Backgrounds: Myeloma‐related bone disease (MBD) is a common complication of multiple myeloma (MM), which can both decrease life quality and influence the prognosis of the patients. We have found that CCN1 stimulated proliferation and differentiation of osteoblasts in MM in vitro and in vivo, while its mechanism still remains unknown. Method: Bone marrow mononuclear cells were collected from MM patients and differentiated into the osteoblasts. After co‐culture with CCN1 in vitro, the intracellular signaling antibody array and western blot were performed to explore the signaling pathway. Furthermore, GSK3β inhibitor TWS119 was used to check the pathway of CCN1 might have on osteoblasts in vitro. Results: For the protein array kit, the expressions of GSK3β, 4E‐BP1, and PTEN are decreased in CCN1 group. For western blots, the CCN1 group also has lower expression comparing to the control group in PTEN (P =.031). Meanwhile p‐AKT and cyclinD1 levels have increased in the CCN1 group (P =.002, P =.039). After adding TWS119 as another group, western blot was performed again to verify the pathway. For upstream proteins PTEN and p‐AKT, TWS119 group has higher expression level compared to that in CCN1 group (P =.003, P =.001). And for downstream protein cyclinD1, TWS119 group also presented higher level than the control group (P =.02). CCN1 could have almost the same effect on GSK3β as the specific inhibitor TWS119 had. Conclusions: CCN1 can stimulate osteoblasts through PTEN/AKT/GSK3β/cyclinD1 pathway in MBD, which has the potential to be a novel therapy of MBD. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated macrophages (TAMs) are originated from circulating mononuclear cells in peripheral blood. They result from the recruitment of tumor cells and are a vital constituent of the tumor microenvironment. TAMs may be involved in the immunological escape of vicious clonal plasma cells (PC) in the bone marrow (BM) of sufferers with myeloma., Methods: From March 2020 to January 2021, 28 healthy controls (HC) and 86 multiple myeloma (MM) (53 newly diagnosed MM [NDMM] and 33 remissions) patients were enrolled as objects of the study. The expression of TAMs in the BM, CSF1 on CD138 + cells, and CSF1R on macrophages were detected by the method of flow cytometry, and the expression of PD-1 on CD8 + T cells and PD-L1 on TAMs were also done. Bone marrow mononuclear cells (BMMNCs) were extracted and cultured into TAMs, CD8 + T cells were sorted by magnetic beads and cultured, a coculture system was established and different inhibitors were added. The expression of the perforin and granzyme B was detected by flow cytometry., Results: The percentage of TAMs in NDMM group (61.49 ± 2.176%) increased when compared with remission (23.08 ± 1.699%, p < 0.001) and HC group (17.95 ± 1.865%, p < 0.001), and TAMs decreased after adding CSF1R inhibitor. Moreover, the expression of CSF1 on CD138 + cells increased significantly in NDMM group (17.090 ± 0.9156%) than remission (8.214 ± 0.5911% p < 0.001), and HC group (5.257 ± 0.6231%, p < 0.001), and CSF1R on macrophages increased significantly in NDMM group (58.78 ± 2.286%) than remission (20.74 ± 1.376%, p < 0.001) and HC group (17.42 ± 1.081%, p < 0.001). The expression of PD-1 on CD8 + T cells in NDMM group (32.64 ± 2.982%) increased than remission (20.35 ± 2.335% p < 0.01) and HC group (17.53 ± 1.349%, p < 0.001), and PD-L1 on TAMs also increased in NDMM group (50.92 ± 2.554%) than remission (20.02 ± 1.893%, p < 0.001) and HC group (13.08 ± 1.289%, p < 0.001). When CD8 + T cells were cocultured with TAMs, the perforin and granzyme B levels decreased significantly. However, the perforin and granzyme B levels were partly restored after adding CSF1R inhibitor and anti-PD-L1 antibody., Conclusion: Our study shows that TAMs were increased in MM patients which can inhibit the function of cytotoxic T lymphocyte (CTL) through the PD-1/ PD-L1 signaling pathway and participate in the occurrence of immune escape of myeloma cells., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)