(A) In OA, constitutive HRH1 signaling contributes to ER stress and increased release of calcium (Ca2⁺) to the cytosol, which serves to stimulate AKT activation. AKT activation leads to phosphorylation of FOXO, causing it to be retained in the cytosol where it is degraded. The resulting decreased levels of FOXO in the nucleus decrease expression of FOXO-regulated genes. HRH1 signaling also activates PLC, which leads to PKC activation and increased p65 phosphorylation, which promotes p65 translocation to the nucleus, increasing transcription of proinflammatory NF-κB–mediated genes. HRH1 also promotes IL-1 signaling as well as an increase in RUNX2-mediated transcription of osteogenesis genes that could promote bone formation seen in OA. Other genes upregulated by HRH1 include those coding for the pain mediator NGF, the calcium channel protein Piezo1, and the calcium binding protein calmodulin. Additional effects of HRH1 include downregulation of PPARγ activity and Insig1 expression, the latter of which results in increased lipogenesis. (B) Cyproheptadine, acting as an inverse agonist, inhibits HRH1 signaling, resulting in increased ER flux. Enhanced ER flux balances calcium levels in the cytosol and increases activity of FOXO3. It also inhibits proinflammatory signaling to reduce expression of OA mediators, an effect also mediated by the increase in FOXO3 and PPARγ.