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Abstract Background Chondromodulin-1 (ChM1), an endogenous anti-angiogenic factor expressed in cartilage, has been suggested to inhibit invasion of endothelial cells into cartilage. In addition, the ectopic administration of ChM1 has been reported to suppress tumorigenesis in vivo. However, it is unclear whether the anti-tumor effect is due to not only the anti-vascularization effect of ChM1, but also its direct action against oncocytes. In the present study, we sought to determine whether ChM1 has a direct action on tumor cells. Methods BrdU incorporation assay was performed on human umbilical vein endothelial cells (HUVECs), normal human dermal fibroblasts (NHDFs), HepG2 cells and HeLa cells in the presence or absence of recombinant human ChM1 (rhChM1). An adenovirus that expresses ChM1, Ad-ChM1, was established and applied to the tumor xenografted in vivo, and to in vitro tumor cells cultured on plates or in soft agar. Cell cycle-related proteins and the phosphorylation of Erk, Akt, and GSK3β, the downstream molecules of the extracellular matrix-integrin signaling pathways, in HepG2 cells treated with or without Ad-ChM1 were detected by western blot analysis. Luciferase reporter assays of STAT, GAS, and ISRE, which participate in another cytokine signaling pathway, ware performed in HepG2, HeLa, and HUVEC cells. Results ChM1 suppressed BrdU incorporation in HUVECs and in HepG2 cells dose-dependently, but did not suppress BrdU incorporation in NHDFs and HeLa cells cultured on plates. In soft agar, however, ChM1 suppressed the growth of HeLa cells, as well as HepG2 cells. Western blot analyses demonstrated that ChM1 decreased the levels of cyclin D1, cyclin D3, and cdk6 and increased those of p21cip1 without affecting the phosphorylation levels of Erk, Akt, and GSK3β in HepG2 cells. The luciferase reporter assay demonstrated that ChM1 suppressed the transcriptional activities of STAT and GAS but not of ISRE. Conclusion ChM1 directly suppressed the proliferation of tumor cells in an anchorage-independent manner. However, ChM1 did not alter the phosphorylation of downstream molecules, at which the signaling pathways through growth factor and cytokine receptors converge with the anchorage-dependent pathway. Our results show that ChM1 has a direct anti-tumor effect; moreover, this effect occurs by inhibiting the STAT signaling pathway.

Since the days of ancient Greece, it has been known that articular cartilage has poor potential to repair. In April, 2013, autologous chondrocyte implantation (ACI) was approved by the Japanese ministry of Health, Labour and Welfare, as the first orthopedic cell therapy in Japan. Half a century has passed since Chesterman's report on rabbit allogeneic chondrocyte implantation, and approximately 20 years since the first human ACI report by Brittberg. In Japan, 24 years has passed since Wakitani's allogeneic chondrocyte implantation, and over 10 years since the human ACI report by Ochi. A long-term follow-up clinical trial with the high statistical power is needed to verify the safety and efficacy of new cartilage joint therapy. Moreover, we need the infrastructure, including drug and/or device regulation and timely approved by the government, to apply new therapies in similar time frames to other developed nations.

Background: Activating Gs a mutations have been identified in most instances of fibrous dysplasia (FD). This mutation leads to consistently elevated intracellular cyclic adenosine monophosphate (cAMP) levels, with various biological consequences. The development of secondary sarcoma in FD is a rare but well-established phenomenon. This finding raised the possibility that a common gene mutation exists in these tumors., Materials and Methods: The expression of the Gs a mutation was examined in 16 cell lines and 173 musculoskeletal tumor tissues, including 13 cases of FD, via RT-PCR and sequence analysis., Results: No expression of a Gs a mutation was detected in any cell line or clinical tissue sample, excluding FD tissues. Direct sequence analysis demonstrated results identical to those of RT-PCR., Conclusion: Activating Gs a mutation rarely occurs in musculoskeletal tumors other than FD. The occurrence of most sarcomas displays no correlation with Gs a mutations.