Link to study in comments. “After COVID, joint pain and bone loss have been reported - a new interesting study proposes a specific link. A signaling peptide from the lungs and a disruption of iron handling. This rests mainly on animal and cell models, the human data are thin. Also relevant for children🧵 The axis. SARS2 infects lung epithelium (spec AT2 cells), which upregulates endothelin-1 (ET-1) - a peptide that normally regulates vascular tone. ET-1 also acts beyond the lungs, disrupting iron handling in cartilage. The authors call this a lung-joint axis. Iron is the connecting thread. In damaged tissue, the iron-uptake receptor TFR1 rises - iron accumulates - triggers oxidative damage (4HNE, lipid peroxidation) - so ferroptosis - iron-dependent cell death. This isn't reduced blood flow, as in ischemic bone necrosis - it's intracellular iron overload and toxicity, not starvation from outside. Cartilage is also avascular, fed by diffusion. A blocked vessel model doesn't mechanically apply here. The strongest causal piece is in vitro. When the authors silenced the ET-1 gene in lung cells, spike protein could no longer trigger iron accumulation in chondrocytes via their conditioned medium. Animal. Hamsters infected intranasally, no steroids. Bone loss and disrupted remodeling (trabecular volume and density) persist through day 30, even as lung viral load declines. The steroid-free model matters - main confounder in COVID bone findings. Endothelin receptors (ETAR/ETBR) also serve spike as an alternative entry route - alongside ACE2, and according to the authors, independent of it. They confirmed direct binding between spike S2 subunit and ETBR wet-lab, not just by modeling. The binding is through S2, not usual RBD. Atypical. So two lines. One is systemic (ET-1 - iron at a distance), the other is direct viral uptake by chondrocytes through ET receptors. Key point. Chondrocytes take up the virus but don't replicate it (abortive, tested WT/Delta/Omicron). So the bone damage isn't coming from virus multiplying in cartilage. Antigen in cartilage. The authors detected spike in human cartilage roughly 7-25 months after infection! Cartilage is avascular and barely turns over - a plausible long term depot. A single method, small sample, and antigen ≠ replicating virus. A depot of residual protein.