Abstract
ABSTRACTThe link between bone and blood vessels is regulated by hypoxia and the hypoxia‐inducible transcription factor, HIF, which drives both osteogenesis and angiogenesis. The recent clinical approval of PHD enzyme inhibitors, which stabilize HIF protein, introduces the potential for a new clinical strategy to treat osteolytic conditions such as osteoporosis, osteonecrosis, and skeletal fracture and nonunion. However, bone‐resorbing osteoclasts also play a central role in bone remodeling and pathological osteolysis, and HIF promotes osteoclast activation and bone loss in vitro. It is therefore likely that the result of PHD enzyme inhibition in vivo would be mediated by a balance between increased bone formation and increased bone resorption. It is essential that we improve our understanding of the effects of HIF on osteoclast formation and function and consider the potential contribution of inhibitory interactions with other musculoskeletal cells. The PHD enzyme inhibitor FG‐4592 stabilized HIF protein and stimulated osteoclast‐mediated bone resorption, but inhibited differentiation of human CD14+ monocytes into osteoclasts. Formation of osteoclasts in a more physiologically relevant 3D collagen gel did not affect the sensitivity of osteoclastogenesis to FG‐4592, but increased sensitivity to reduced concentrations of RANKL. Coculture with osteoblasts amplified inhibition of osteoclastogenesis by FG‐4592, whether the osteoblasts were proliferating, differentiating, or in the presence of exogenous M‐CSF and RANKL. Osteoblast coculture dampened the ability of high concentrations of FG‐4592 to increase bone resorption. These data provide support for the therapeutic use of PHD enzyme inhibitors to improve bone formation and/or reduce bone loss for the treatment of osteolytic pathologies and indicate that FG‐4592 might act in vivo to inhibit the formation and activity of the osteoclasts that drive osteolysis. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
The skeletal system and the vasculature are strongly linked during bone development, skeletal aging and in bone pathologies such as osteoporosis, osteonecrosis and skeletal fracture and non-union [1]
FG-4592 stimulates osteoclast bone resorption but reduces differentiation Of the classical non-specific PHD enzyme inhibitors which include dimethyl oxalyl glycine (DMOG), Lmimosine, desferrioxamine and CoCl2, DMOG causes the greatest increase in osteoclast-mediated bone resorption, despite some evidence of toxic effects [19, 22]
While 3D monoculture did not alter the effect of FG-4592 on osteoclast differentiation, 2D co-culture with osteoblasts caused marked inhibition of osteoclastogenesis by FG-4592 as well as diminished stimulation of bone resorption
Summary
The skeletal system and the vasculature are strongly linked during bone development, skeletal aging and in bone pathologies such as osteoporosis, osteonecrosis and skeletal fracture and non-union [1]. Skeletal cells secrete angiogenic factors to stimulate new blood vessel formation. In turn skeletal blood vessels supply osteoblastic bone-forming cells with oxygen, nutrients, growth factors and essential mineralisation components such as calcium and phosphate, maintain stem and progenitor cells and regulate skeletal cell behaviour. The link between blood vessels and bone is regulated by hypoxia and the hypoxia-inducible transcription factor, HIF [2, 3]. Under standard conditions HIF-α is post-translationally hydroxylated by the prolyl-4-hydroxylase enzymes (PHD1–3), targeting it for interaction with the von Hippel–Lindau (VHL) protein and proteasomal degradation. HIF- accumulates, translocates to the nucleus, dimerizes with HIF-β and binds the hypoxia-response element to induce transcription of HIF target genes such as pro-angiogenic vascular endothelial growth factor (VEGF) (reviewed in [4])
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