Systemic Dysfunction of Osteoblast Differentiation in Adipose-Derived Stem Cells from Patients with Multiple Myeloma.

Véronique Béréziat,Indira Toillon,Annette K Larsen,Michèle Sabbah,François Delhommeau,Martine Auclair,Nathalie Ferrand,Laurent Garderet,Bruno Fève,Séverine Jolly,Christelle Mazurier,Tiffany Marie,Ladan Kobari

doi:10.3390/cells8050441

Abstract

Multiple myeloma is characterized by bone lesions linked to increased osteoclast and decreased osteoblast activities. In particular, the osteoblast differentiation of bone marrow-derived stem cells (MSC) is impaired. Among the potential therapeutic tools for counteracting bone lesions, adipose-derived stem cells (ASC) could represent an appealing source for regenerative medicine due to their similar characteristics with MSC. Our study is among the first giving detailed insights into the osteoblastogenic capacities of ASC isolated by fat aspiration from myeloma patients (MM-ASC) compared to healthy subjects (HD-ASC). We showed that MM-ASC and HD-ASC exhibited comparable morphology, proliferative capacity, and immunophenotype. Unexpectedly, although normal in adipocyte differentiation, MM-ASC present a defective osteoblast differentiation, as indicated by less calcium deposition, decreased alkaline phosphatase activity, and downregulation of RUNX2 and osteocalcin. Furthermore, these ASC-derived osteoblasts displayed enhanced senescence, as shown by an increased β-galactosidase activity and cell cycle inhibitors expression (p16INK4A, p21WAF1/CIP1.), associated with a markedly increased expression of DKK1, a major inhibitor of osteoblastogenesis in multiple myeloma. Interestingly, inhibition of DKK1 attenuated senescence and rescued osteoblast differentiation, highlighting its key role. Our findings show, for the first time, that multiple myeloma is a systemic disease and suggest that ASC from patients would be unsuitable for tissue engineering designed to treat myeloma-associated bone disease.

Highlights

Multiple myeloma (MM) is the most frequent malignant hematological disease, after non-Hodgkin’s lymphoma, and represents 13% of all malignant hematological disorders, corresponding to approximately 115,000 new cases and 80,000 deaths yearly, worldwide [1]
INK4 expression of the cell cycle inhibitors p21 and p16 cycle inhibitors p21 and p16 (Figure 5C and Supplementary Figure S2). These findings indicated that MM-marrow-derived stem cells (MSC) and MM-adipose-derived stem cells (ASC) derived from the same donor were comparable with regard to adipocyte and osteoblast differentiation
For the first time, that stem cells at sites distant from the bone marrow, namely in adipose tissue, display defective osteoblastic differentiation, they are capable of normal adipocyte differentiation

Summary

Introduction

Multiple myeloma (MM) is the most frequent malignant hematological disease, after non-Hodgkin’s lymphoma, and represents 13% of all malignant hematological disorders, corresponding to approximately 115,000 new cases and 80,000 deaths yearly, worldwide [1]. MM is associated with severe malignancy of the bone marrow, incurable in most cases. In the majority of cases, the symptoms are dominated by lytic bone lesions and may be accompanied by anemia, renal failure, and/or metabolic manifestations, such as hypercalcemia [2]. MM-associated bone disease (MMBD) is the signature of MM and results from persistent uncoupling of the normal bone remodeling process, including increased osteoclast and attenuated osteoblast activities [3,4,5]. Bisphosphonates are used to prevent and slow down lytic bone lesion [6,7]. They correct hypercalcemia and reduce bone pain with less need for pain-killers. Since MMBD is responsible for the most deleterious complications of MM, it is essential to develop new therapeutic strategies to combat this destructive process

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