Protein S-palmitoylation in osteoarticular cell signalling and metabolic adaptation

Protein S-palmitoylation is a reversible lipid post-translational modification that dynamically controls protein localization, trafficking, receptor microdomain organization, autophagy and metabolic signalling. In osteoarticular tissues, this modification provides a plausible biochemical mechanism through which osteoclasts, osteoblast-lineage cells, osteocytes, chondrocytes, synoviocytes and skeletal-muscle cells integrate inflammatory, mechanical and metabolic cues. This review synthesizes current evidence linking S-palmitoylation and depalmitoylation to osteoarticular cell signalling and metabolic adaptation. We focus on experimentally supported mechanisms, including ZDHHC-mediated palmitoylation; depalmitoylation by APT, ABHD and PPT enzymes; palmitoylation-sensitive osteoclast differentiation; inflammatory priming of macrophage-derived osteoclast precursors; BMP/SMAD and organelle-contact-site signalling in osteoblast-lineage cells; ZDHHC11-dependent chondrocyte protection; ZDHHC4-mediated palmitoylation of CCDC50 followed by autophagic clearance of MAP2K4/MKK4; inflammasome regulation; CD36-associated lipid uptake; and palmitoylation-dependent transporter localization and turnover. We distinguish direct skeletal and joint evidence from mechanistic analogues derived from immune, neural, metabolic and cancer systems. We also clarify the distinction between reversible cysteine S-palmitoylation, broader S-acylation and other lipid modifications. Major barriers include incomplete definition of enzyme and substrate relationships, false-positive risk in palmitoyl-proteomic workflows, limited temporal resolution, insufficient validation in primary human tissues, uncertain tissue specificity and the off-target effects of non-selective palmitoylation inhibitors. A cell-biochemistry-centred view of the dynamic balance between palmitoylation and depalmitoylation may clarify how lipid modification regulates osteoarticular cell function and may help prioritize experimentally testable, substrate-specific mechanisms for future validation in osteoarthritis, osteoporosis and inflammatory joint disease.