Impaired osteoblastogenesis potential of progenitor cells in skeletal unloading is associated with alterations in angiogenic and energy metabolism profile
Issue title: Papers from the 6th Scientific Meeting on Cartilage Engineering, October 2011, Nancy, France
Affiliations: Laboratory of Bioengineering and Biomechanics for Bone Articulation, Faculty of Medicine, University Paris Diderot, Paris, France | Department of Prosthetic Dentistry/BIOMAT Research Cluster, School of Dentistry, Oral Pathology and Maxillofacial Surgery, Faculty of Medicine, Leuven, Belgium | Département de Soutien Médico-Chirurgical des Forces, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France
Note: [] Address for correspondence: Katleen Vandamme, Laboratory of Bioengineering and Biomechanics for Bone Articulation, Faculty of Medicine, University Paris Diderot, 10 Avenue de Verdun, 75010 Paris, France. Tel.: +33 1 57 27 85 58; Fax: +33 1 57 27 85 71; E-mail: [email protected].
Abstract: Skeletal unloading provokes bone loss. These bone alterations have been shown to be associated with impairment of osteoblastic activity. In the present study, we evaluated the effect of skeletal unloading on bone marrow progenitor cells, for exploration of the underlying mechanism. Wistar rats were randomized to be either hindlimb unloaded for 9 days or to act as controls. Micro-CT was used to detect tibial trabecular architecture changes in response to skeletal unloading. Microgravity conditions for 9 days resulted in a decreased number and an increased spacing of the bone trabeculae in the proximal tibia. The proliferative capacity of the femoral bone marrow samples was assessed (fibroblast-colony-forming assay). By using qPCR, the expression of selected markers of vascularization (Vegfa; Hif1a; Angpt1), energy metabolism (Prkaa2; Mtor), bone formation (Runx2; Alp; Bglap; Bmp2; Bmp4; Bmp7) and bone resorption (Acp5; Tnfsf11; Tnfrsf11b) in these bone marrow suspensions was measured. We demonstrated a striking decrease in the number of fibroblastic progenitors in response to hindlimb unloading. This deficit in proliferation was shown to be accompanied by altered hindlimb perfusion and cellular energy homeostasis. Ex vivo culture assays of the bone marrow-derived progenitor cells screened for osteogenic (Runx2; Alp; Bglap) and adipogenic (Pparg; Fabp4) differentiation alterations in response to microgravity. Induced progenitor cells from unloaded rats showed a delay in osteogenic differentiation and impaired adipogenic differentiation compared to control. The data of this multi-level approach demonstrate that skeletal unloading significantly affects the bone tissue and its metabolism at the progenitor stage. The molecular expressions of the bone marrow population support a role of cellular metabolic stresses in skeletal alterations induced by inactivity.
Keywords: Skeletal unloading, progenitor cells, perfusion and energy metabolism, differentiation, multi-scale assessment
