Lubricin (PRG4) in Articular Cartilage and Intervertebral Disc: Comparative Biology and Therapeutic Potential.

OBJECTIVE: Lubricin (proteoglycan 4, PRG4) is a multifunctional glycoprotein with well-established roles in articular cartilage (AC) homeostasis-including boundary lubrication, anti-adhesion, cytoprotection, and anti-inflammatory modulation through NF-κB and TLR-dependent pathways. Despite two decades of research, its biology in the intervertebral disc (IVD) remains underexplored, and no prior review has systematically compared lubricin's expression, function, and regulation across these two load-bearing tissues. DESIGN: Literature was identified through searches of PubMed/MEDLINE, Web of Science, and Scopus through January 2026. The full keyword combination included primary terms 'lubricin,' 'PRG4,' alongside historical synonymous aliases 'SZP (superficial zone protein)' and 'MSF (megakaryocyte stimulating factor precursor)', plus tissue and disease keywords 'articular cartilage,' 'intervertebral disc,' 'osteoarthritis,' and 'disc degeneration.' Notably, papers solely indexed under SZP or MSF are scarce, and nearly all publications referencing these aliases also feature PRG4/lubricin in abstract or full text. As a narrative comparative review, formal PRISMA-based screening was not applied; primary research articles were prioritized. RESULTS: Lubricin is expressed in both AC and IVD, with tissue- and species-specific distributions: in humans it spans all disc compartments (annulus fibrosus, nucleus pulposus, and cartilaginous endplate), whereas in goats it is restricted to the outer AF, likely reflecting greater bipedal axial loading in humans. Lubricin functions as a boundary lubricant in AC and as an interlamellar lubricant and anti-inflammatory mediator in the IVD; Prg4-deficient mice develop elevated disc torsional modulus and early degenerative spondylosis, confirming its structural role in the spine. Regulatory mechanisms in AC are well-defined, involving TGF-β/SMAD, Wnt/β-catenin, EGFR/Creb5, FoxO1, and mechanosensitive pathways; IVD regulation is governed primarily by hypoxia, TLR2-mediated cytokine suppression, and ECM-dependent feedback, with key transcription factors largely uncharacterized in disc cells. CONCLUSIONS: Emerging therapeutic strategies-gene therapy, recombinant PRG4 supplementation, small-molecule modulators, and lubricin-functionalized biomaterials-show promise for both osteoarthritis (OA) and IVD degeneration (IVDD), though each faces tissue-specific translational barriers. PRG4-expressing NP progenitor cells, lubricin glycoform characterization, and IVD-specific regulatory circuits represent priority research areas to advance lubricin-targeted therapies for degenerative musculoskeletal disease.