Background/Purpose: Oxygen supply is a fundamental requirement for all living tissues. Some tissues such as articular joints are characterized by a physiological state of hypoxia. Interestingly, under conditions of inflammation such as in arthritic disease, this level of hypoxia is even further enhanced. However, the functional significance of these observations and the molecular mechanisms involved remain poorly characterized to date. We therefore examined the role of 3 known oxygen sensors, prolyl hydroxylase domain (PHD) proteins: PHD1, PHD2 and PHD3. They are enzymes whose function is essentially controlled by oxygen. Their expression pattern varies between either of them and all of them have been ascribed specific roles in a myriad of biological processes. Our goal was to examine the role of oxygen sensors PHD1, PHD2 and PHD3 in preclinical models of rheumatoid arthritis, and to delineate the cellular source involved.

Methods: We subjected the collagen antibody induced arthritis (CAIA) model (resembling rheumatoid arthritis) to hypoxic (10% O2) and normoxic conditions (21% O2), respectively. Furthermore, the CAIA-model was induced in mice with germline deficiency of the specific PHD’s and in mice with a myeloid cell-specific PHD1 deficiency versus controls. Arthritis development was assessed by clinical scoring of paw swelling, histopathology of knee joints and μCT.

Results: Mice kept in hypoxic conditions during CAIA experiments showed markedly less arthritis (both by clinical and histopathological assessment) compared to mice in normoxic conditions. Furthermore, we demonstrated that PHD1 knock-out (KO) mice had significantly less joint inflammation compared to wildtype mice. PHD1 KO mice were also protected against inflammation induced bone loss as evidenced by μCT. By contrast, no differences were found between PHD2 heterozygous (PHD2 KO mice are not viable) or PHD3 KO mice and littermate controls. Because myeloid cells are considered critical effector cells upon passive transfer of arthritogenic antibodies in the CAIA model we also generated myeloid cell specific ko mice (PHD1myelKO). Of interest, PHD1myelKO mice developed less arthritis compared to wildtype mice and were protected against inflammation induced bone loss.

Conclusion: Our data are consistent with a new paradigm that the oxygen sensor PHD1 is a critical regulator of myeloid cell function in arthritic disease. Overall, the data suggest that PHD1 is a potential target in the treatment of arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-oxygen-sensor-phd1-is-an-indispensable-regulator-of-arthritis-development/