AlJamal-Naylor, R. | Search bioRxiv

bioRxiv2026

Allosteric modulation of β1 integrin through the hybrid domain reverses articular cartilage injury and functional impairment in a murine model of inflammatory arthritis

Rheumatoid arthritis is a chronic inflammatory joint disease in which progressive destruction of cartilage and bone drives long-term disability. Current disease-modifying therapies target the immune and cytokine networks that sustain synovial inflammation, but none is directed at the chondrocyte, the resident cell responsible for maintaining cartilage matrix. Chondrocyte survival and matrix homeostasis depend on {beta}1-integrin-mediated adhesion to the extracellular matrix, and dysregulated integrin signalling has been implicated in cartilage injury. Here we test the hypothesis that allosteric modulation of {beta}1 integrin, rather than simple adhesion blockade, is chondroprotective. Using the monoclonal antibody JB1a, which binds an epitope in the hybrid domain of {beta}1 integrin and stabilises the receptor in a low-affinity conformation, we show that intra-articular administration produces both functional and structural amelioration of Freunds complete adjuvant (FCA)-induced arthritis in mice. JB1a abolished the FCA-induced increase in joint diameter and hyperalgesia and markedly reduced synovial inflammation, pannus formation and cartilage erosion, with no effect on the contralateral joint and no observed adverse effects. These changes were accompanied by a reduction in chondrocyte apoptosis in vivo. In primary human articular chondrocytes, JB1a abolished interleukin-1{beta} (IL-1{beta})-induced caspase 3/7 activation, reduced IL-8 secretion, and restored the sinusoidal oscillation of intracellular ATP that was otherwise abrogated by IL-1{beta}. In contrast, the adhesion-blocking, integrin-clustering antibody 6S6 activated caspase 3/7 and amplified IL-1{beta}-induced IL-8 secretion, indicating that the therapeutic effect is a property of the specific mode of receptor engagement rather than of adhesion blockade per se. These findings identify {beta}1-integrin conformational state as a determinant of chondrocyte energy homeostasis and survival, and nominate allosteric {beta}1-integrin modulation as a mechanistically distinct, chondrocyte-directed therapeutic strategy in inflammatory arthritis.

pharmacology and toxicology↗

bioRxiv2026

Allosteric Modulation of β1 Integrin Attenuates Motor Asymmetry in the Unilateral 6-Hydroxydopamine Injury Model in Mice

Parkinsons disease (PD) is characterised by progressive dopaminergic neurodegeneration in the substantia nigra, leading to debilitating motor dysfunction. Current treatments remain largely symptomatic, highlighting the need for disease-modifying therapies. {beta}1 integrin, implicated in neuroinflammation and trophic signalling, represents a candidate therapeutic target. We investigated whether allosteric {beta}1 integrin modulation could attenuate motor asymmetry in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of PD. Adult male C57BL/6 mice received intracerebral 6-OHDA into the substantia nigra. The anti-{beta}1 integrin antibody JB1a (50 {micro}g) was administered prophylactically (3 days pre-lesion) or therapeutically (3 or 7 days post-lesion). Motor asymmetry was assessed through spontaneous circling (5 min) and apomorphine-induced (0.5 mg/kg s.c.) circling (30 min). 6-OHDA induced dose-dependent contralateral circling, confirming nigrostriatal lesion. Pre-treatment with JB1a (3 days before 6-OHDA) reduced apomorphine-induced circling, although this did not reach statistical significance (28.5 {+/-} 12.8, n = 4 versus 38.6 {+/-} 7.5, n = 8; p>0.05). Post-treatment at 3 days post-lesion produced no statistically significant change in either spontaneous or apomorphine-induced circling (p>0.05). Post-treatment at 7 days post-lesion reduced apomorphine-induced circling by approximately 50%, with values returning to those of sham-operated controls (n =8-9; p<0.01). These findings, obtained in a murine 6-OHDA model, indicate that allosteric {beta}1 integrin modulation attenuates lesion-induced motor asymmetry with apparent temporal specificity. As apomorphine-induced rotation reflects post-synaptic dopamine receptor supersensitivity rather than direct neuronal preservation, and as histological confirmation of dopaminergic integrity was not obtainable in this study, the present data should be interpreted as proof-of-concept behavioural evidence requiring further mechanistic and translational validation in models incorporating -synuclein pathology. The findings are not directly generalizable to human Parkinsons disease. The histological confirmation of lesion extent was not available and as such the behavioural findings are correspondingly interpreted as a proof-of-concept observation requiring histological replication.

neuroscience↗