Osteoarthritis (OA) is the most common chronic joint disorder worldwide, with a high personal burden for the patients and an important socio-economic impact. Current therapies are largely limited to pain management and rehabilitation and exercise strategies. For advanced cases, joint replacement surgery may be the only option. Hence, there is an enormous need for the development of effective and safe disease-modifying anti-OA drugs. A strong focus in OA research has been on the identification and role of molecular signalling pathways that contribute to the balance between anabolism and catabolism in the articular cartilage. In this context, most insights have been gained in understanding the roles of the transforming growth factor-beta (TGF-β) and the Wingless-type (Wnt) signalling cascades. The emerging picture demonstrates a high degree of complexity with context-dependent events. TGF-β appears to protect cartilage under healthy conditions, but shifts in its receptor use and subsequent downstream signalling may be deleterious in aged individuals or in damaged cartilage. Likewise, low levels of Wnt activity appear important to sustain chondrocyte viability but excessive activation is associated with progressive joint damage. Emerging clinical data suggest some potential for the use of sprifermin, a recombinant forms of fibroblast growth factor 18, a distant TGF-β superfamily member, and for lorecivivint, a Wnt pathway modulator.

Osteoarthritis is the most prevalent joint disease worldwide, and it is a leading source of pain and disability. To date, this disease lacks curative treatment, as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identified transcription factors and networks that regulate DOT1L gene expression using a potentially novel bioinformatics pipeline. Thereby, we unraveled a possibly undiscovered link between the hypoxia pathway and DOT1L. We provide evidence that hypoxia enhanced DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 α (HIF1A). Importantly, we demonstrate that DOT1L contributed to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restored DOT1L function and stalled disease progression. Collectively, our data unravel a molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.

Mice harbouring a dentin matrix protein 1 (Dmp1) promoter-driven human diphtheria toxin (DT) receptor (HDTR) transgene (Tg) have recently been used to attain targeted ablation of osteocytes by diphtheria toxin (DT) treatment in order to define osteocyte function. Use of these Tg mice has asserted mechano- and novel paracrine regulatory osteocyte functions. To explore osteocyte roles fully, we sought to confirm the selectivity of DT effects in these transgenic mice. However, our findings revealed incomplete DT-induced osteocyte ablation, prevalent HDTR misexpression, as well as more prominent histopathological DT-induced changes in multiple organs in Tg than in wild-type (WT) littermate mice. Mechanistic evidence for DT action, via prominent regulation of phosphorylation status of elongation factor-2 (EF-2), was also found in many non-skeletal tissues in Tg mice; indicative of direct "off-target" DT action. Finally, very rapid deterioration in health and welfare status in response to DT treatment was observed in these Tg when compared to WT control mice. Together, these data lead us to conclude that alternative models for osteocyte ablation should be sought and caution be exercised when drawing conclusions from experiments using these Tg mice alone.