Kosei Ando

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies.

Mifamurtide for the treatment of nonmetastatic osteosarcoma

Introduction: The standard treatment for osteosarcoma requires both macroscopic surgical wide resection and postoperative multi-drug chemotherapy in neoadjuvant and adjuvant settings. However, the 5-year event-free survival has remained at a plateau of 60 – 70% of patients with nonmetastatic osteosarcoma for more than 30 years. Areas covered: Mifamurtide (liposomal muramyl tripeptide phosphatidylethanolamine; L-MTP-PE) is a new agent. L-MTP-PE is a nonspecific immunomodulator, which is a synthetic analog of a component of bacterial cell walls. L-MTP-PE activates macrophages and monocytes as a potent activator of immune response in addition to standard chemotherapy. It also improves the overall survival from 70 to 78% and results in a one-third reduction in the risk of death from osteosarcoma. This review summarizes the most recent findings about L-MTP-PE and its therapeutic application for nonmetastatic osteosarcoma. Expert opinion: Recently, L-MTP-PE has been approved in Europe for the treatment of nonmetastatic osteosarcoma with chemotherapy. L-MTP-PE in combination with traditional treatment is expected to go mainstream and to be beneficial for patients with osteosarcoma. Information about potential benefit regarding mifamurtide use in the neoadjuvant setting (i.e., before surgery) and/or usefulness of L-MTP-PE in metastatic in relapsed and metastatic osteosarcoma requires analysis of expanded access and/or future clinical trials of L-MTP-PE in high-burden and low-burden situations.

Chondroitin sulfate for the treatment of hip and knee osteoarthritis: current status and future trends.

AIMS Osteoarthritis (OA) is a common joint disorder and a major socio-economic burden. Chondroitin sulfate (CS), which has chondroprotective properties, is a promising candidate for the therapeutic treatment of OA. Here, we summarize current knowledge as well as future trends of CS for the treatment of hip and knee OA. MAIN METHODS We retrospectively reviewed pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of CS for the treatment of OA. KEY FINDINGS The safety and tolerability of CS are confirmed. CS is effective, at least in part, for the treatment of OA, and its therapeutic benefits occur through three main mechanisms: 1) stimulation of extracellular matrix production by chondrocytes; 2) suppression of inflammatory mediators; and 3) inhibition of cartilage degeneration. SIGNIFICANCE CS is a safe and tolerable therapeutic agent for the management of OA. Its effects include benefits that are not achieved by current medicines and include chondroprotection and the prevention of joint space narrowing. Such positive effects of CS represent a breakthrough in the treatment of hip and knee OA.

A novel exogenous concentration-gradient collagen scaffold augments full-thickness articular cartilage repair

OBJECTIVES A collagen scaffold has been long used in order to enhance the regeneration of articular cartilage. In the present study, we investigate the effectiveness of a concentration-gradient (CG) collagen that is designed to recruit efficiently the mesenchymal stem cells (MSCs) to the central region of the full-thickness cartilage defects via haptotaxis. METHODS The present study used Cellmatrix (0.3% type I collagen; Nitta gelatin, Osaka, Japan) as the collagen material. We prepared 33%CG collagen gel and 50%CG collagen gel. No gradient collagen gel served as negative control. Full-thickness cartilage defects were created at the patella groove of the rabbit knee, to which the three different collagen gels were transplanted. Bromodeoxyuridine (BrdU) positive, proliferating cells were enumerated and localized, whereas the histological grading score for cartilage regeneration was counted. The expression of type I and type II collagens was evaluated by immunohistochemistry. We also confirmed that the MSCs migrate toward the collagen substrate of higher concentration in a stringently in vitro haptotactic manner. RESULTS Enumeration of the BrdU-positive cells demonstrated that 33%CG collagen gel recruited a significantly larger number of proliferating cells to the central region of the cartilage defect. The histological grading score for the regenerated cartilage treated with 33%CG collagen gel was superior to the other groups. CONCLUSIONS CG collagen scaffold recruits effectively the MSCs to the center of full-thickness cartilage defect and enhances regeneration of the full-thickness cartilage defect.

RANKL/RANK/OPG: Key Therapeutic Target in Bone Oncology

Cancer is one of the major leading causes of death all over the world. Primary and secondary bone tumors can significantly deteriorate the quality of life (QOL) and the activity of daily living (ADL) of the patients. These unwelcome diseases become a social and economic burden seriously. Thus, more effective therapies for both primary and secondary bone tumors are actually required. Bone homeostasis depends on the strictly balanced activities between bone formation by osteoblasts and bone resorption by osteoclasts. Imbalance of bone formation and resorption results in various bone diseases. Both primary and secondary bone tumors develop in the unique environment bone, it is therefore necessary to understand bone cell biology in tumoral bone environment. Recent findings strongly revealed the significant involvement of the receptor activator of nuclear factor kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad, the key regulators of bone remodeling in bone oncology. Indeed, RANKL/RANK blocking successfully prevented the development of bone metastases. Furthermore, some cancer cells express RANK which is involved in tumor cell migration. Thus, the regulation of this triad will be a rational, encouraged therapeutic hot spot in bone oncology. In this review, we summarize the accumulating knowledge of the RANKL/RANK/OPG triad and discuss about its therapeutic capability in primary and secondary bone tumors.

Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases

Osteosarcoma is the most common form of primary malignant bone tumor. The use of chemotherapy drugs with many side effects, including high-dose methotrexate, doxorubicin, cisplatin and ifosfamide, has greatly improved osteosarcoma survival compared with surgery alone. However, for 20 years, overall survival remained at a plateau of 60–70% in nonmetastatic disease and 20–30% in metastatic osteosarcoma owing to lung metastases. Liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE) is a new agent that improves overall osteosarcoma survival (chemotherapy without L-MTP-PE 70% versus with L-MTP-PE 78%; p = 0.03). L-MTP-PE offers additional benefit for osteosarcoma treatment in combination with chemotherapy, particularly ifosfamide-containing regimens. Clinical experience indicates that side effects such as fever are temporary and controlled or prevented with ibuprofen and/or acetoaminophen premedication; severe side effects are rare. Although surgery will remain the main approach for osteosarcoma treatment of lung metastases, L-MTP-PE combined with other modalities, including chemotherapy, appears to be of benefit in these patients as well.

Molecular Alterations Associated with Osteosarcoma Development

Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion, survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently, recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for osteosarcoma treatment to improve the clinical outcome.

Effect of dynamic compressive loading and its combination with a growth factor on the chondrocytic phenotype of 3-dimensional scaffold-embedded chondrocytes

Background and purpose Three-dimensionally (3D-) embedded chondrocytes have been suggested to maintain the chondrocytic phenotype. Furthermore, mechanical stress and growth factors have been found to be capable of enhancing cell proliferation and ECM synthesis. We investigated the effect of mechanical loading and growth factors on reactivation of the 3D-embedded chondrocytes. Methods Freshly isolated chondrocytes from rat articular cartilage were grown in monolayer cultures and then in collagen gel. Real-time RT-PCR and histological analysis for aggrecan and type II and type I collagen was performed to evaluate their chondrocytic activity. Then, the 3D-embedded chondrocytes were cultured under either mechanical loading alone or in combination with growth factor. The dynamic compression (5% compression, 0.33 Hz) was loaded for 4 durations: 0, 10, 60, and 120 min/day. The growth factor administered was either basic fibroblast growth factor (bFGF) or bone morphogenetic protein-2 (BMP-2). Results Mechanical loading statistically significantly reactivated the aggrecan and type II collagen expression with loading of 60 min/day as compared to the other durations. The presence of BMP-2 and bFGF clearly enhanced the aggrecan and type II collagen expression of 3D-embedded chondrocytes. Unlike previous reports using monolayer chondrocytes, however, BMP-2 or bFGF did not augment the chondrocytic phenotype when applied together with mechanical loading. Interpretation Dynamic compression effectively reactivated the dedifferentiated chondrocytes in 3D culture. However, the growth factors did not play any synergistic role when applied with dynamic compressive loading, suggesting that growth factors should be administered at different time points during regeneration of the transplantation-ready cartilage.

Exogenous collagen-enhanced recruitment of mesenchymal stem cells during rabbit articular cartilage repair

Background Despite the well-known effect of type-I collagen in promoting cartilage repair, the mechanism still remains unknown. In this study we investigated this mechanism using a rabbit model of cartilage defects. Animals and methods 5-mm-diameter full-thickness defects were created on both patellar grooves of 53 Japanese white rabbits (approximately 13 weeks old). The left defect was filled with collagen gel and the right defect was left empty. The rabbits were killed and examined morphometrically until the twenty-fourth postoperative week, by (1) evaluation of matrix production, (2) enumeration of the total number of cells engaged in cartilage repair, (3) enumeration of the proliferating cells, (4) localization of mesenchymal stem cells, and (v) localization of apoptotic cells. Results We found that type-I collagen enhances cell recruitment, and thereby increases the number of proliferating cells. A considerable proportion of the proliferating cells were identified as bone marrow-derived mesenchymal stem cells. However, type-I collagen does not prevent the chondrocyte precursors from undergoing apoptotic disengagement from the chondrogenic lineage. Interpretation Type-I collagen promotes cartilage repair by enhancing recruitment of bone marrowderived mesenchymal stem cells. Additional use of agent(s) that sustain mesenchymal stem cells along the chondrogenic path of differentiation may constitute an appropriate environment for cartilage repair.

Conditioned media from mouse osteosarcoma cells promote MC3T3-E1 cell proliferation using JAKs and PI3-K/Akt signal crosstalk

The maintenance of bone mass requires a strict balance between bone formation by osteoblasts and bone resorption by osteoclasts. In tumoral bone environment, tumor cells frequently disturb this balance by interaction with bone cells to create a favorable site for tumor growth, and promote pathological bone changes. Thus, elucidation of the mechanisms underlying interaction between tumor cells and bone cells might eventually lead to a more rational strategy for therapeutic intervention for bone tumors and better understanding of bone biology. In the present study, the effects of mouse osteosarcoma cells on mouse preosteoblastic cells were determined by assessment of cell viability, osteoblastic differentiation and signal transduction pathways. MOS‐J/POS‐1 conditioned media (CM) significantly induced MC3T3‐E1 cell proliferation in a dose‐dependent manner and reduced both alkaline phosphatase activity and mineralized nodule formation. Piceatannol, AG490, LY294002 and rapamycin significantly abrogated this up‐regulated cell proliferation; however, UO126 and STAT3 inhibitor peptide did not affect this up‐regulated cell proliferation. MOS‐J/POS‐1 CM activated ERK 1/2, STAT3 and Akt signal transduction pathways; however, pro‐proliferating signal induced by MOS‐J/POS‐1 CM was transmitted via Akt not ERK 1/2 and STAT3 pathways. Furthermore, Western blot analyses clearly revealed novel signal crosstalk between JAKs and PI3‐K/Akt in osteoblastic cells. The specific factor(s) involved in MOS‐J/POS‐1 CM‐induced MC3T3‐E1 cell proliferation that use JAKs/PI3‐K/Akt/mTOR pathway remain(s) to be determined. Determination of the specific factor(s) responsible for JAKs and PI3‐K/Akt signal crosstalk that results in up‐regulated preosteoblast proliferation will offer new insight into the pathology of osteosarcoma as well as other bone‐related diseases. (Cancer Sci 2008; 99: 2170–2176)