Osteoporosis: the current status of mesenchymal stem cell-based therapy

Abstract

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.

Keywords: Cell therapy; MSCs; Mesenchymal stem cells; Osteoporosis; Stem cells.

Fig. 1

Bone homeostasis regulation by OPG/RANK/RANKL system. RANKL which secreted by activated T cells functions as an osteoclast-activating factor by binding to its receptor, RANK, which is expressed on preosteoclasts. RANKL-RANK binding induces the activation of several transcription factors in preosteoclasts and initiates several downstream signaling pathways that drive osteoclast differentiation and maturation. OPG which secreted by osteoblasts, bone marrow stromal cells, and T reg cells acts as a soluble receptor that can bind to RANKL and subsequently prevents RANKL-RANK binding. Under physiologic conditions, OPG/RANKL is in equilibrium and preserves bone homeostasis. Under osteoporotic conditions, RANKL is upregulated, which is associated with downregulation of OPG. Several proinflammatory cytokines are secreted from T helper cells (Th1/Th2/Th17) stimulating and upregulating RANKL expression and mediating osteoclast formation and activity, which are linked to increased bone resorption