ORIGINAL ARTICLE: RESEARCH Mesenchymal stem cell abnormalities in patients with multiple myeloma LAURENT GARDERET 1,2 , CHRISTELLE MAZURIER 1 , ALAIN CHAPEL 1,3 , ISABELLE ERNOU 4 , LAETITIA BOUTIN 4 , XAVIER HOLY 5 , NORBERT CLAUDE GORIN 1,2 , MANUEL LOPEZ 1 , CHRISTELLE DOUCET 4 , & JEAN-JACQUES LATAILLADE 4 1 INSERM, U832, EA1638, Paris, F-75012 France, Universite ´ Pierre et Marie Curie-Paris 6, Site de Saint Antoine, 27 rue Chaligny, Paris, F-75012 France, 2 Hematology Department, Saint Antoine Hospital (APHP), 186 rue du Faubourg St Antoine, F-75012 France, 3 IRSN, BP 17, 92262 Fontenay aux Roses Cedex, France, 4 Research Department, Jean Julliard Army Blood Transfusion Centre, 1 rue Lieutenant Raoul Batany, BP 410, 92141 Clamart Cedex, France, and 5 Aerospace Physiology Department, Aerospace Medical Institute, Army Health Service, BP 73, 91223 Bre ´tigny sur Orge Cedex, France (Received 9 June 2007; revised 23 June 2007; accepted 19 July 2007) Abstract Osteolytic bone lesions are common in patients with multiple myeloma (MM), a clonal plasma cell disorder, and result from increased osteoclastic bone resorption and decreased osteoblastic bone formation. Because mesenchymal stem cells (MSCs) are committed towards cells of the osteoblast lineage, we compared the in vitro characteristics of MSCs from the bone marrow of 18 MM patients (MM-MSCs) and eight normal donors (ND-MSCs). MM-MSCs displayed deficient growth that could be explained in part by the reduced expression of several growth factor receptors on the surface of MM-MSCs compared with ND-MSCs. Receptor downregulation was observed on RT-PCR analysis. A major finding was an approximately fivefold higher expression of osteoblast inhibitor DKK1 at transcript and protein levels in MM-MSCs than ND-MSCs. These data suggest that defective osteoblast function in patients with advanced MM may be related not only to factors released by tumor myeloma cells but also to MSC abnormalities. Keywords: Multiple myeloma, mesenchymal stem cells, osteoblasts, bone lesions Introduction Multiple myeloma (MM) is a clonal plasma cell disorder characterized by the synthesis of an abnor- mal paraprotein, bone destruction, immunodefi- ciency, and renal impairment [1]. Over 85% of MM patients have osteolytic bone disease which can cause severe pain, fractures, spinal cord compres- sion, and hypercalcemia [2,3]. As the tumor pro- gresses, the bone lesions increase. Bone is a dynamic tissue in which osteoblasts synthesize bone matrix, while osteoclasts resorb bone. Under normal physiological conditions, the balance between bone resorption and formation is maintained through a complex regulatory system of both systemic and local factors. In MM, osteoclas- togenesis is enhanced, leading to bone destruction, whereas osteoblast production is impaired, leading to suppressed bone reconstruction [4]. Several cyto- kines and growth factors produced by either myelo- ma cells or stromal cells have been implicated in increased osteoclast formation [5,6]. A key cytokine is IL-6 since it both activates osteoclasts and promotes tumor growth, but there are also others that activate osteoclasts and suppress osteoblast function, thus leading to uncompensated bone destruction [7]. The mechanism of reduced bone formation in MM patients has not yet been com- pletely elucidated [8]. Inhibition of osteoblast for- mation and differentiation may, for instance, be due Correspondence: Dr. Manuel Lopez, Service d’he ´matologie, Faculte ´ de Me ´decine Saint Antoine, 27, rue Chaligny, 75571 Paris Cedex 12, France. Fax: þ33-1-40011386. E-mail: manuel.lopez@chusa.jussieu.fr Leukemia & Lymphoma, October 2007; 48(10): 2032 – 2041 ISSN 1042-8194 print/ISSN 1029-2403 online Ó 2007 Informa UK Ltd. DOI: 10.1080/10428190701593644 Leuk Lymphoma Downloaded from informahealthcare.com by INSERM on 09/01/10 For personal use only.