Thrombospondin-1 Regulates Bone Homeostasis Through Effects on Bone Matrix Integrity and Nitric Oxide Signaling in Osteoclasts

Abstract

Thrombospondin-1 (TSP1), an endogenous antiangiogenic, is a widely expressed secreted ligand with roles in migration, adhesion and proliferation and is a target for new therapeutics. While TSP1 is present in the bone matrix and several TSP1 receptors play roles in bone biology, the role of TSP1 in bone remodeling has not been fully elucidated. Bone turnover is characterized by coordinated activity of bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OC). TSP1−/− mice had increased bone mass and increased cortical bone size and thickness compared to wild type (WT). However, despite increased size, TSP1−/− femurs showed less resistance to bending than expected, indicative of diminished bone quality and a bone material defect. Additionally, we found that TSP1 deficiency resulted in decreased OC activity in vivo and reduced OC differentiation. TSP1 was critical during early osteoclastogenesis, and TSP1 deficiency resulted in a substantial overexpression of inducible nitric oxide synthase (iNOS). Importantly, administration of a NOS inhibitor rescued the OC function defects of TSP1−/− mice in vivo. To investigate the role of bone-derived TSP1 in osteoclastogenesis, we found that wild type (WT) pre-OCs had defective iNOS expression when cultured on TSP1−/− bone compared to WT bone, suggesting that TSP1 in bone plays a critical role in iNOS signaling during OC development. These data implicate a new role for TSP1 in bone homeostasis with roles in maintaining bone matrix integrity and regulating OC formation. It will be critical to monitor bone health of patients administered TSP1-pathway directed therapeutics in clinical use and under development.

miR-218 is involved in the negative regulation of osteoclastogenesis and bone resorption by partial suppression of p38MAPK-c-Fos-NFATc1 signaling: Potential role for osteopenic diseases

“…During the differentiation of osteoclasts from hematopoietic precursors, the monocytic cells must migrate and fuse together to form multinucleated mature osteoclasts [4]. Convincing evidence indicates that osteoclasts exert a critical role in maintaining bone homeostasis by replacing old bones with new bones through coordinating with osteoblasts [5,6]. Therefore, understanding the underlying mechanism involved in osteoclast differentiation and activation processes is urgently needed for the treatment of osteopenic diseases.…”

“…As a new class of gene regulators, they are correlated with the wide range of biological processes including cell differentiation, growth, migration and invasion by inversely regulating target gene transcription or translation [6][7][8]. Mounting evidence indicates that abnormal expression of miRNAs is emerging as the prominent pathological contributor for bone degeneration-related diseases by regulating the process of osteoclastogenesis and bone resorption [9][10][11].…”

Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

“…Bone marrow macrophage (BMM) cultures were isolated from C57Bl/6J mice, plated and maintained in macrophage media culture for 3 days (MEM alpha, Life Technologies + 10% FBS + and 100ng/mL M-CSF) 34 . Osteoclasts were cultured 6 days in macrophage media (described above) + RANKL (50ng/ml) following isolation of BMMs 35, 36 . Cell viability was measured using MTT assay (Sigma-Aldrich, St. Louis, MO, USA) 35 .…”

The Role of the Molecular Clock in Skeletal Muscle and What It Is Teaching Us About Muscle-Bone Crosstalk

“…CircaDB (circadb hogeneschlab.org39]Gene symbolCircadian in muscle (p < 0.05)Changed in iMS Bmal1 −/− (p < 0.05)Bone formationBone resorptionUpregulated Fndc5Yes0.0457Promotes osteoblast differentiation [58•] VegfaYes0.0269Enhances osteoclast differentiation and survival of mature osteoclasts [59] SparcNo0.0202Promotes bone mineralization [60] Tgfb1No0.0142Induce endochondral bone formation and mineralization [61] Ccl9No0.0435Induces osteoclast accumulation at resorptive sites [62] Anxa5Yes0.0124Promotes pre-osteoblast proliferation [63] Ltbp4No0.0010Modifies availability of TGFB1 [64] Thbs1Yes0.0232Promotes resorption but mechanism is still unclear [65] Igfbp4Yes0.0185Inhibits osteoblast function by sequestering IGF, thus, inhibiting bone formation [66]Downregulated Il15No0.0178Stimulates pre-osteoclast differentiation and decreases bone resorption by inducing natural killer cell-mediated osteoclast apoptosis [67, 68] MstnNo0.0041Negatively regulates bone formation [69]Upregulates RANKL-induced osteoclast development [70•] Hmgb1No0.0238Potent resorption signal [71] Igfbp5No0.0084Stimulates bone formation and may function independently of IGFs [72]Stimulates osteoclast function by augmenting IGF-1 [72] Gdf11Yes0.0010Inhibits osteoblast differentiation [73]Stimulates osteoclastogenesis [73] …”