In Paget's disease of bone (PDB), a major contributory factor are osteoclasts (OCs) that are larger, more numerous, resistant to apoptosis, and hyperactive. The aim of this human in vitro study was to identify kinase cascades involved in the OC phenotype and to determine their impact on downstream processes. Basal phosphorylation levels of Akt and ERK were found to be elevated in PDB OCs. Given our previous findings that 3-phosphoinositide-dependent protein kinase 1 (PDK1) associates with the crucial adaptor p62 in OCs, we hypothesized that PDK1 may play an important role in OC-related kinome regulation. The increased phosphorylation of Akt and its substrate GSK3b observed in PDB OCs was reduced significantly upon PDK1 inhibition, as well as that of 4EBP1 and Raptor. This suggests a PDK1/Akt-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) in PDB OCs. The resistance to apoptosis and the bone resorption were also overcome upon PDK1 inhibition. Studying autophagy by LC3B expression, we found a less inducible autophagy compared with control cells, which was reversed by PDK1 inhibition. In addition, PBD OCs exhibited higher LC3B-II/LC3B-I ratios and numbers of p62 and LC3B puncta per OC area, which did not further increase in the presence of lysosomal protease inhibitors, suggesting an accumulation of non-degradative autophagosomes. Together these results indicate a strong potential regulatory role for PDK1 in OC stimulatory pathways (Akt, ERK) and autophagy induction (via mTORC1), which may contribute to the OC phenotype in PDB. We also identified defects in late autophagosome maturation in these cells, the mechanism of which remains to be determined.

Objective Cannabis is increasingly used for medical purposes, particularly in countries like Canada where cannabis was recently legalized for recreational use. We aimed to assess self-medication with cannabis post-cannabis legalization among adults in the Canadian province of Quebec. Methods This is a cross-sectional online survey of a self-selected convenience sample conducted in Quebec, Canada, from November 2020 to January 2021. Individuals aged ≥ 21 years who endorsed using cannabis bought in legal recreational cannabis stores to self-medicate a health condition were included. Data were analyzed using descriptive statistics and stratified according to sex, age, and the type of cannabis use (exclusively medical versus medical and recreational use). Results Four hundred eighty-nine participants were included. The median age was 34 years, and 48% were women. About 25% reported exclusive medical use of cannabis. Treated conditions included anxiety (70%), insomnia (56%), pain (53%), depression (37%), and many others. Reasons for not consulting in cannabis clinics included lack of information (52%), the complexity of the process (39%), accessibility of cannabis clinics (23%), and others. Tetrahydrocannabinol (THC) dosage > 20% was reported by 32%. Smoking was the main route of use (81%). Possession of prescribed drugs was reported by 56%. Professionals consulted for information on cannabis included recreational cannabis store agents (36%), physicians (29%), and others. Overall, significant differences were observed for many of the comparisons according to sex, age, and the type of cannabis use. Conclusions Many conditions are self-medicated with cannabis. The use of high doses of cannabis, smoking as a preferred method of use, and concurrent use of other medications may pose some risks to individuals. Addressing the reported barriers to medical access to cannabis is urgently needed.

Objective Little is known about self-medication with cannabis post-recreational cannabis legalization in Canada. We aimed to establish a detailed portrait of self-medication with cannabis among adults in Quebec. Methods We conducted an online survey from November 2020 to January 2021 among individuals aged ≥ 21 years, who endorsed using cannabis bought in legal recreational cannabis stores to self-medicate a health condition. Data were analysed using descriptive statistics and stratified according to sex, age and the type of cannabis use (exclusively medical versus medical and recreational use). Results 489 participants were included. Median age was 34 years, and 48% were women. About 25% reported an exclusive medical use of cannabis. Treated conditions included anxiety (70%), insomnia (56%), pain (53%), depression (37%), and many other. Reasons for not consulting in cannabis clinics included lack of information (52%), complexity of the process (39%), accessibility of cannabis clinics (23%) and other.