Hypoxia signalling manipulation for bone regeneration

Abstract

Hypoxia-inducible factor (HIF) signalling is intricately involved in coupling angiogenesis and osteogenesis during bone development and repair. Activation of HIFs in response to a hypoxic bone micro-environment stimulates the transcription of multiple genes with effects on angiogenesis, precursor cell recruitment and differentiation. Substantial progress has been made in our understanding of the molecular mechanisms by which oxygen content regulates the levels and activity of HIFs. In particular, the discovery of the role of oxygen-dependent hydroxylase enzymes in modulating the activity of HIF-1α has sparked interest in potentially promising therapeutic strategies in multiple clinical fields and most recently bone healing. Several small molecules, termed hypoxia mimics, have been identified as activators of the HIF pathway and have demonstrated augmentation of both bone vascularity and bone regeneration in vivo. In this review we discuss key elements of the hypoxic signalling pathway and its role in bone regeneration. Current strategies for the manipulation of this pathway for enhancing bone repair are presented with an emphasis on recent pre-clinical in vivo investigations. These findings suggest promising approaches for the development of therapies to improve bone repair and tissue engineering strategies.

Enhanced osteogenesis and angiogenesis by mesoporous hydroxyapatite microspheres-derived simvastatin sustained release system for superior bone regeneration

“…HIF-1 is a transcription factor composed of 2 subunits, HIF-1α and HIF-1β, and HIF-1α acts as a cellular oxygen sensor that induces a response to low oxygen tension. Activation of the HIF pathway stimulates the transcription of multiple hypoxia response genes, among which VEGF is a major target44. It was reported that simvastatin could protect HIF-1α from degradation by inhibiting prolyl-4-hydroxylase 3 (PHD-3), which hydroxylates the two proline residues in the oxygen-dependent degradation domain of HIF-1α under normoxic conditions and leads to interactions with the von Hippel-Lindau (VHL) ubiquitin ligase complex that promotes ubiquitin-mediated proteolysis of the HIF-1α subunit45.…”

Hypoxia-Mimicking Nanofibrous Scaffolds Promote Endogenous Bone Regeneration

“…31 In addition to angiogenesis, immobilized DFO may promote osteogenesis through other angiogenesis-independent ways because multiple targets were reported once HIFs signaling pathway was activated. 40,41 Furthermore, many studies reported that hypoxic conditions are able to directly modulate MSC proliferation and differentiation to osteoblasts, though controversial results were noted, which have been summarized in a recent review article. 41 We did not find that DFO could directly increase hMSCs osteogenic differentiation in vitro (data not shown).…”

“…40,41 Furthermore, many studies reported that hypoxic conditions are able to directly modulate MSC proliferation and differentiation to osteoblasts, though controversial results were noted, which have been summarized in a recent review article. 41 We did not find that DFO could directly increase hMSCs osteogenic differentiation in vitro (data not shown). Further studies are needed to understand the potential mechanisms by which DFO/HIF-1’s direct effects on MSCs functions for osteogenic differentiation.…”

Short-Term Hypoxia Accelerates Bone Loss in Ovariectomized Rats by Suppressing Osteoblastogenesis but Enhancing Osteoclastogenesis

“…The hypoxic microenvironment has been considered as a vital factor for the hypoxia-induced factor (HIF-1)-dependent angiogenesis that is critical for bone formation during bone development and regeneration after trauma [18,19]. Consistently, bone marrow stromal cell differentiation and osteoblastogenesis can be inhibited by hypoxic culture in vitro [20].…”