Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases

Abstract

Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction-oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O₂^-) and hydrogen peroxide (H₂O₂), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.

Keywords: osteoclast differentiation; osteoclasts; osteoporosis; reactive oxygen species.

Figure 1

RANKL/RANK signaling pathway from stromal cells/OBs showing downward signaling molecules to the transcription factors in the nucleus that regulate OC differentiation. RANKL is an important cytokine in the OC signal pathway together with various intracellular signaling molecules—such as TRAF, MAPKs, NF-κB, and NFATc1—which are essential for regulating OC differentiation.

Figure 2

ROS generation by mitochondria can influence various biological functions but excessive production of ROS lead to signaling alteration, membrane damage, release of cytochrome c, and oxidative damage to mitochondrial proteins and DNA. Consequently, oxidative damage can impair synthesis of ATP thereby preventing normal metabolic functions which contributes to a wide range of disease development.