Hyaluronan, lubricin and phospholipids, molecules ubiquitous in synovial joints, such as hips and knees, have separately been invoked as the lubricants responsible for the remarkable lubrication of articular cartilage; but alone, these molecules cannot explain the extremely low friction at the high pressures of such joints. We find that surface-anchored hyaluronan molecules complex synergistically with phosphatidylcholine lipids present in joints to form a boundary lubricating layer, which, with coefficient of friction μ≈0.001 at pressures to over 100 atm, has a frictional behaviour resembling that of articular cartilage in the major joints. Our findings point to a scenario where each of the molecules has a different role but must act together with the others: hyaluronan, anchored at the outer surface of articular cartilage by lubricin molecules, complexes with joint phosphatidylcholines to provide the extreme lubrication of synovial joints via the hydration–lubrication mechanism.

Measurements of normal and shear (frictional) forces between mica surfaces across small unilamellar vesicle (SUV) dispersions of the phosphatidylcholine (PC) lipids DMPC (14 : 0), DPPC (16 : 0) and DSPC (18 : 0) and POPC (16 : 0, 18 : 1), at physiologically high pressures, are reported. We have previously studied the normal and shear forces between two opposing surfaces bearing PC vesicles across pure water and showed that liposome lubrication ability improved with increasing acyl chain length, and correlated strongly with the SUV structural integrity on the substrate surface (DSPC > DPPC > DMPC). In the current study, surprisingly, we discovered that this trend is reversed when the measurements are conducted in SUV dispersions, instead of pure water. In their corresponding SUV dispersion, DMPC SUVs ruptured and formed bilayers, which were able to provide reversible and reproducible lubrication with extremely low friction (μ < 10⁻⁴) up to pressures of 70–90 atm. Similarly, POPC SUVs also formed bilayers which exhibited low friction (μ < 10⁻⁴) up to pressures as high as 160 atm. DPPC and DSPC SUVs also provided good lubrication, but with slightly higher friction coefficients (μ = 10⁻³–10⁻⁴). We believe these differences originate from fast self-healing of the softer surface layers (which are in their liquid disordered phase, POPC, or close to it, DMPC), which renders the robustness of the DPPC or DSPC (both in their solid ordered phase) less important in these conditions. Under these circumstances, the enhanced hydration of the less densely packed POPC and DMPC surface layers is now believed to play an important role, and allows enhanced lubrication via the hydration lubrication mechanism. Our findings may have implications for the understanding of complex biological systems such us biolubrication of synovial joints.

Objective: To identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at the ALDH1A2 locus, which is a retinoic acid regulatory gene.Methods: Tissue samples from 247 patients with knee, hip, or hand OA who had undergone joint surgery were included. RNA‐sequencing analysis was used to investigate differential expression of ALDH1A2 and other retinoic acid signaling pathway genes in cartilage. Expression of ALDH1A2 in joint tissues obtained from multiple sites was quantified using quantitative reverse transcription–polymerase chain reaction. Allelic expression imbalance (AEI) was measured by pyrosequencing. The consequences of ALDH1A2 depletion by RNA interference were assessed in primary human chondrocytes. In silico and in vitro analyses were used to pinpoint which, among 62 highly correlated SNPs, could account for the association at the locus.Results: ALDH1A2 expression was observed across multiple joint tissue samples, including osteochondral tissue from the hand. The expression of ALDH1A2 and of several retinoic acid signaling genes was different in diseased cartilage compared to non‐diseased cartilage, with ALDH1A2 showing lower levels in OA cartilage. Experimental depletion of ALDH1A2 resulted in changes in the expression levels of a number of chondrogenic markers, including SOX9. In addition, reduced expression of the OA risk–conferring allele was witnessed in a number of joint tissues, with the strongest effect in cartilage. The intronic SNP rs12915901 recapitulated the AEI observed in patient tissues, while the Ets transcription factors were identified as potential mediators of this effect.Conclusion: The ALDH1A2 locus seems to increase the risk of hand OA through decreased expression of ALDH1A2 in joint tissues, with the effect dependent on rs12915901. These findings indicate a mechanism that may now be targeted to modulate OA risk.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2 , which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.