Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Abstract

In the growing skeleton, angiogenesis is intimately coupled with osteogenesis. Chronic, high doses of glucocorticoids (GCs) are associated with decreased bone vasculature and induce osteoporosis and growth failure. The mechanism of GC‐suppression of angiogenesis and relationship to osteoporosis and growth retardation remains largely unknown. Type H vessels, which are regulated by preosteoclast (POC) platelet‐derived growth factor–BB (PDGF‐BB), are specifically coupled with bone formation and development. We determined the effect of GCs on POC synthesis of PDGF‐BB in relation to type H vessel formation, bone mass, and bone growth in the distal femur of 2‐week‐old young mice receiving prednisolone or vehicle for 2, 4, or 6 weeks. After 2 weeks of prednisolone, the number of POCs were unchanged while POC synthesis of PDGF‐BB was reduced. Longer treatment with prednisolone reduced POCs numbers and PDGF‐BB. These changes were associated with a reduction in type H vessels, bone formation rate, bone mass, and bone length at each time point. In vitro, excessive concentrations of prednisolone (10−6M) resulted in decreased PDGF‐BB concentration and POC numbers. Conditioned medium from POC cultures treated with control concentration of prednisolone (10−7M) or recombinant PDGF‐BB stimulated endothelial tube formation, whereas conditioned medium from control concentration of prednisolone‐treated POC cultures neutralized by PDGF‐BB antibody or excessive prednisolone inhibited endothelial tube formation. Administration of excessive prednisolone attenuated the P65 subunit of nuclear factor kappa B (NF‐κB) binding to the Pdgfb promoter, resulting in lower Pdgfb transcription. Co‐treatment with excessive prednisolone and the glucocorticoid receptor (GR) antagonist (RU486), GR siRNA, or TNFα rescued NF‐κB binding to the Pdgfb promoter and endothelial tube formation. These results indicate that PDGF‐BB synthesis in POCs is suppressed by GCs through transrepression of GR/NF‐κB, thus inhibiting type H vessel formation and associated osteoporosis and growth failure. © 2020 American Society for Bone and Mineral Research.

Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis

“…It has long been recognized that exogenous GCs have divergent effects on osteoclasts both in vivo and in vitro due to differences in strain, age, glucocorticoid dose, or experimental set-up 93 . Our finding that MPS treatment decreases osteoclast numbers in femoral metaphysis in growing young mice is consistent with previous work conducted using the same age of young mice 74,75 .…”

“…Metaphyseal vascular cells and osteoprogenitors undergo senescence in response to GC treatment. It is well-recognized that angiogenesis coupled with osteogenesis is abundant in the metaphysis of the growing skeleton in mice but declines in young adult mice, in which bone growth slows 71,[73][74][75] . Therefore, it is logical to postulate that highly proliferative vascular cells and osteoprogenitor cells in metaphysis are particularly vulnerable to GC treatment.…”

An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP+ mononuclear cells and PDGF-BB secretion

“… 26 , 27 A recent study showed that NF-ĸB can bind to the Pdgfb promoter in preosteoclasts and is necessary for the induction of PDGF-BB expression. 28 Interestingly, Siglec-G negatively regulated the activation of NF-ĸB. It is unknown whether Siglec-15 has a similar effect to that of Siglec-G in regulating the signals of NF-ĸB.…”

Autocrine Activity of Extracellular Vesicles Induced by Icariin and Its Effectiveness in Glucocorticoid-Induced Injury of Bone Microvascular Endothelial Cells

“…Meanwhile, exogenous glucocorticoid administration is the principal iatrogenic cause for secondary osteoporosis and nontraumatic osteonecrosis of the femoral head (ONFH), which adds a tremendous economic burden to individuals and healthcare systems [ 1 , 2 ]. In patients with glucocorticoid-induced bone loss, angiogenesis is suppressed, accompanied by circulatory impairment, persistent bone destruction, increased apoptosis of osteocytes, disrupted balance of mesenchymal stem cells’ (MSCs) differentiation, fat embolism, and intramedullary pressure changes [ 3 , 4 ].…”