Biology subjects

Gonzalez-Nolde, S.

Publications and source records attributed to Gonzalez-Nolde, S..

3 recordsLinked to original sources

bioRxiv2026

Thrombospondin-2 deficiency primes the synovial joint for aberrant tissue remodeling and injury response

ObjectiveThis study investigates joint injury-induced angiogenesis and the effects of genetic deficiency of thrombospondin-2 (TSP2), an anti-angiogenic factor, in joint homeostasis and post-traumatic osteoarthritis (PTOA). MethodWe utilized a murine non-invasive anterior cruciate ligament rupture (ACLR) model of PTOA and mined published synovial transcriptomics datasets to investigate injury-induced synovial angiogenesis. Spatial transcriptomics and flow cytometry of TSP2-GFP reporter mice were used to assess injury-induced thrombospondin-2 and its cellular origins in synovium. Global TSP2 knockout mice (TSP2-KO) were used to assess the effect of TSP2 deficiency on early and late stages of PTOA development via molecular imaging of inflammation and angiogenesis, histopathology, micro-computed tomography, Raman spectroscopy, and synovium bulk RNA-sequencing. ResultsIntra-articular angiogenesis peaked at 7d post-ACLR and declined but remained elevated above baseline at 28d post-ACLR. We identified synovial crosstalk between endothelial cells and sublining fibroblasts as a key driver of angiogenesis and source of thrombospondin-2 signaling, with TSP2 primarily upregulated in sublining fibroblasts. TSP2-KO mice exhibited increased peri-articular inflammation at 7d post-ACLR and inferior bone quality. Histopathology revealed greater PTOA severity but paradoxically lower synovitis in TSP2-KOs. Additionally, aberrant structural remodeling of the entire knee joint was observed in uninjured and ACLR TSP2-KO limbs. The uninjured TSP2-KO synovial transcriptome demonstrated elevated immune, fibrotic, and angiogenic activation; however, TSP2-KO and WT synovial transcriptomes partially converged upon injury. ConclusionTSP2 is essential for joint homeostasis and trauma response. Global TSP2 deficiency causes premature OA and worsened PTOA, suggesting that therapeutic targeting with TSP2 mimetic could be used to prevent OA.

physiology↗

bioRxiv2025

CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis

This study investigates the role of the chemokine CXCL16 and its receptor, CXCR6, in post-traumatic osteoarthritis (PTOA) and joint nociception, highlighting the potential of targeting the CXCL16-CXCR6 axis for therapeutically managing joint inflammation and pain. Following joint injury in mice, the CXCL16-CXCR6 signaling axis is activated in synovium, driven by synovial fibroblasts and macrophages. Human OA synovium also exhibited increased CXCL16 and CXCR6 gene expression. CXCL16 stimulated a pro-inflammatory response in fibroblasts and macrophages, contrasting with an anti-inflammatory response observed in mesenchymal progenitor cells. In mice, repeated intra-articular CXCL16 injections induced histological synovitis and sex-dependent activation of inflammatory and fibrotic transcriptional programs in synovium. Repeated CXCL16 joint injections also induced knee hyperalgesia, which was mitigated by co-administration of the CXCR6 antagonist, ML339. A single intra-articular injection of CXCL16 induced acute knee hyperalgesia as early as 30 minutes post-injection, which was completely abrogated by ML339 co-treatment, suggesting direct CXCL16 binding to nociceptor-expressed CXCR6. In a murine PTOA model, systemic CXCR6 antagonism with ML339 alleviated knee hyperalgesia and altered circulating immune cell profiles. Direct stimulation of mouse dorsal root ganglion-derived nociceptive neurons with CXCL16 induced rapid calcium signaling, which was abolished by co-treatment with ML339. These findings establish CXCL16 as a regulator of joint inflammation and identifies the CXCL16-CXCR6 binding mechanism as key in mediating pain-related behaviors and nociceptor activation, offering a therapeutic target for PTOA-related inflammation and pain management. One Sentence SummaryCXCL16 regulates synovial inflammation and mediates joint nociception via CXCR6, highlighting its potential as a therapeutic target for post-traumatic osteoarthritis.

physiology↗

bioRxiv2025

A standardized, open-source, portable model for noninvasive joint injury in mice

Preclinical models of osteoarthritis (OA) are crucial for the study of disease mechanisms and for the development of critically-needed disease-modifying therapeutics. While surgical OA models, such as the destabilization of the medial meniscus (DMM), have been the gold standard in the field for decades, noninvasive joint loading-based models have increased in popularity and utility. To facilitate standardization of the noninvasive anterior cruciate ligament rupture (ACLR) model in mice, we present the Mobile Joint-Injury Operator (MoJO) - an open-source protocol with accompanying fixtures and data, designed for a low-cost, commercially-available, portable uniaxial testing system with a small footprint. We provide 3d-printable fixture designs and a rapid, highly-repeatable ACLR-mediated joint injury protocol that results in the expected post-traumatic osteoarthritis phenotype in male and female C56Bl/6 mice. We then describe the expected mechanical data from the injury procedure and offer various troubleshooting strategies. Finally, we summarize the resultant PTOA phenotype by knee hyperalgesia testing, {micro}CT imaging, flow cytometry, and histological assessment. Increased standardization of this model is a critical aspect of the overall refinement of animal models of OA.

physiology↗