The osteoclast is hematopoietic in origin and is the primary bone-resorbing cell derived from monocyte/macrophage lineage. Tumor necrosis factor (TNF) family member, RANK ligand (RANKL) expressed on marrow stromal/osteoblast cells in response to several osteotropic factors, is critical for osteoclast precursor differentiation to form multinucleated osteoclasts, which resorb bone. M-CSF is required for proliferation, survival, and expression of receptor activator of nuclear factor kappa B (RANK) in osteoclast precursors. The interaction of RANKL-RANK results in activation of various signaling cascades during osteoclast development and activation. The osteoclast is an autocrine/paracrine, intracrine regulatory cell that produces factors such as IL-6, Annexin II, TGF-β, OIP-1/hSca, which influence its own formation and activity. In addition, integrin expression in osteoclasts mediate cell-matrix and cell-cell interactions in the bone microenvironment through specific signaling pathways resulting in cytoskeletal organization, polarization, and activation of osteoclasts to resorb bone. Recent molecular genetic studies have identified several transcription factors, such as NF-κB, c-Fos, MITF, and NFATc1, which are essential for osteoclast differentiation. Although a wide variety of molecules, including the reactive oxygen species (ROS) that are differentially regulated during osteoclastogenesis, the precise signal transduction pathways, and molecular mechanisms underlying the gene expression in osteoclasts, are just beginning to be defined. In this review, we discuss the molecular regulatory mechanisms operative during osteoclast differentiation, bone resorption, and survival.

CXC chemokine ligand-13 (CXCL13) has been implicated in oral squamous cell carcinoma (OSCC) tumor progression and osteolysis. The tumor necrosis factor family member RANKL (receptor activator of NF-κB ligand), a critical bone resorbing osteoclastogenic factor, has an important role in cancer invasion of bone/osteolysis. Here, we show high-level expression of CXCL13 in primary human OSCC tumor specimens; however, human bone marrow-derived stromal (SAKA-T) and murine preosteoblast (MC3T3-E1) cells produce at very low level. Recombinant CXCL13 (0–15 ng/ml) dose dependently induced CXCR5 expression in SAKA-T and MC3T3-E1 cells. Conditioned media obtained from OSCC cell lines increased the RANKL expression and an antibody against the CXCL13 specific receptor, CXCR5 markedly decreased RANKL expression in these cells. Furthermore, CXCL13 increased hRANKL-Luc promoter activity. Superarray screening identified c-Myc and NFATc3 transcription factors upregulated in CXCL13-stimulated SAKA-T cells. Immunohistochemical analysis of OSCC tumors that developed in athymic mice demonstrated RANKL and NFATc3 expression in tumor and osteoblast cells, however, showed p-c-Myc expression specific to osteoblastic cells at the tumor–bone interface. We further identified NFATc3 expression, but not c-Myc activation in primary human OSCC tumor specimens compared with adjacent normal tissue. Also, CXCL13 significantly increased p-ERK1/2 in SAKA-T and MC3T3-E1 cells. siRNA suppression of c-Myc expression markedly decreased CXCL13-induced RANKL and NFATc3 expression in preosteoblast cells. Chromatin-immuno precipitation assay confirmed p-c-Myc binding to the hRANKL promoter region. In summary, c-Myc activation through CXCL13–CXCR5 signaling axis stimulates RANKL expression in stromal/preosteoblast cells. Thus, our results implicate CXCL13 as a potential therapeutic target to prevent OSCC invasion of bone/osteolysis.

Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in bone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell-specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy. Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity.