The balance between bone-forming osteoblasts and bone-resorbing osteoclasts helps to preserve the integrity of skeleton and bone. The osteoclast takes charge of the removal of the organic component and inorganic component of bone. Despite the small proportion it occupies in bone cells, osteoclast can help to maintain the normal skeletal strength obviously relying on various activities. Nevertheless, the formation and resorption of osteoclast bring in pathological stimulation, thereby causing many diseases including postmenopausal osteoporosis, inflammatory arthritis, cancer bone metastasis, etc (1). For investigating the differentiation and activity of osteoclast, raw 264.7 has become a valueable tool relying on its expression of RANK and differnentiation to the osteoclast affected by RANKL (2). A series of endocrine hormones together with metabolic signals can regulate the process. New understanding of the regulation of osteoclastogenesis and bone resorption will contribute to better treatment method as well as effective insights into the pathology of disease (1).
The insulin-like growth factor-1 (IGF-1) system remarkably affects the bone remodeling. IGFBP-1 is one of six IGFBPs, which bind to and regulate bioavailability of IGF-1. Apart from decreasing bone formation by inhibition of IGF-1 actions, IGFBP-1 can also promote bone resorption by stimulating osteoclast differentiation, by IGF-1-independent mechanisms (3). In brief, IGFBP-1 is a pro-osteoclastogenic liver hormone induced by FGF21, which binds to its receptor Integrin β1 on the osteoclast precursors, thereby playing its function, so as to potentiate the Erk-phosphorylation as well as NFATc1 activation stimulated by RANKL (3). Clinical finding indicates that high IGFBP-1 was related to the increasing fracture risk, unrelated to IGF-1 or BMI but partially mediated by the BDM, which supports the abovementioned effect of IGFBP-1 (4). In addition, when compared with control subjects of age and sex, the concentration of IGFBP-1 for osteoporosis patients was four times higher (5). Meanwhile, IGFBP-1 is an BAK-binding regulator of apoptosis in hepatocytes (6). RGD peptides block the integrin interaction with the bone matrix, thereby accelerating the apoptosis of osteoclast (7). So it can be speculated that IGFBP-1 may affect osteoclastogenesis, at least in part, via the apoptosis pathway.
Apoptosis, as an important mechanism, is applied by mechanism to removing unnecessary cells for precisely controlling the development and function of organ. Accumulation of ROS may trigger apoptosis via many apoptotic signaling pathways, particularly apoptotic pathways dependent of mitochondria. Abovementioned apoptotic events dependent of mitochondria are under the mediation of Bcl-2 family of proteins which determine the destiny of cells through anti-apoptosis (Bcl-2, Bcl-X, Bcl-w, etc.) as well as pro-apoptosis (Bax, Bad, Bak, etc.) members (8). Based on recent finding about animals and clinical studies, there is an obvious association between the oxidative stress and ROS and the pathogenesis regarding bone loss related to age (9, 10). ROS is able to damage the mitochondrial unltrastructure as well as destroy its function, thereby activating the caspase-3 via different molecular cascade reactions and activate mitochondrial apoptotic pathway. Therefore, researchers are suggested to focus on the relation between apoptosis induced by ROS and osteoclastogenesis induced by IGFBP-1.
As found in the study, IGFBP-1 could promote RANKL-induced osteoclastogensis via evaluating IGFBP-1 on TRAP staining as well as the expression of a lot of marker genes. IGFBP-1 could inhibit cell apoptosis via reducing intracellular ROS genertion and inhibiting signaling pathway dependent of mitochondria. All these could inhibit the formation and function of mature osteoclast.