Biology subjects

Collins, K. H.

Publications and source records attributed to Collins, K. H..

5 recordsLinked to original sources

bioRxiv2026

Leptin Drives Osteoarthritis Pain Through Sensory Neuron Reprogramming Independent of Cartilage Signaling

ObjectivePain in osteoarthritis (OA) is often discordant with structural joint damage, particularly in obesity-associated OA, where adipose-derived signals may drive nociception independently of cartilage pathology. Leptin has been demonstrated to be necessary, but not sufficient, to drive obesity-associated OA. Here, we tested the hypothesis that leptin mediates OA-associated pain through sensory neuron reprogramming rather than chondrocyte-intrinsic signaling, suggesting a fat-sensory nerve axis. DesignMale and female constitutive leptin-deficient (Ob/Ob), heterozygous (Ob/+), and wild-type (WT) mice, as well as chondrocyte-specific leptin receptor knockout mice (Aggrecan-CreERT2;LepRfl/fl), were challenged with destabilization of the medial meniscus (DMM) surgery to induce OA. Pain-related behaviors, joint pathology, serum cytokines, and lumbar dorsal root ganglia (DRG) transcriptomes were assessed. Human DRG cultures treated with leptin underwent transcriptomic profiling. Secondary analyses of human infrapatellar fat pad and synovium single-cell datasets evaluated leptin and leptin receptor expression patterns. ResultsChondrocyte-specific deletion of the leptin receptor did not mitigate OA pathology or pain. Global leptin-deficient (Ob/Ob) mice exhibited worse structural joint outcomes than WT and Ob/+ animals following DMM yet were robustly protected from OA-associated hyperalgesia - directly dissociating pain from structural pathology and demonstrating that leptin is involved in nociceptive sensitization. Serum cytokine profiles were sex-dependent and did not align with pain outcomes, separating systemic inflammation from nociceptive differences. Transcriptomic analysis of DRGs revealed that leptin drives enrichment of lipid metabolism, eicosanoid, and inflammatory programs, whereas leptin deficiency shifts sensory neurons toward a cytoskeletal remodeling state that does not sustain pain signaling. In human DRG cultures, leptin treatment produced a transcriptomic shift to enrich for neuronal excitability while vehicle treated cells were enriched for inflammatory signaling. Human infrapatellar fat pad and synovium transcriptomic data demonstrated adipocyte-enriched leptin expression and broad distribution of the leptin receptor across stromal, vascular, immune, and adipocyte populations. ConclusionsLeptin contributes to OA pain through neuro-immune crosstalk between adipose tissue and sensory neurons rather than through direct cartilage signaling. These findings identify leptin-associated neuronal programs linked to nociceptor sensitization and support targeting leptin-modulated neuro-immune pathways as a strategy to alleviate OA pain independently of structural disease progression.

physiology↗

bioRxiv2026

Adipose-driven complement-lipid reprogramming controls nociceptive vulnerability in obesity-associated osteoarthritis

Obesity amplifies osteoarthritis (OA) pain disproportionately to joint damage, creating a major unmet clinical need for non-opioid interventions that act beyond the joint. Using OA as a translational model, we integrated serum multi-omics in obese mice with surgically induced OA and genetic and adipose-reconstitution models of complement factor D (FD). In humans, we analyzed longitudinal metabolomics data from the IDEA weight-loss trial and conducted functional studies in dorsal root ganglion (DRG) neurons. Adipose-derived FD emerged as a regulator of systemic immunometabolic state: FD deficiency in obese mice worsened pain sensitivity whereas restoring circulating FD normalized pain and inflammatory markers without altering joint structure. Cross-species lipid profiling identified conserved shifts in linoleic acid versus arachidonic acid-derived lipids that were associated with pain phenotypes in mice and with pain improvement in humans. Defined lipid cocktails modulated excitability and TRPV1 sensitivity in human DRG neurons, and transcriptomics of knee-innervating DRGs revealed diet and FD-dependent activation of complement and neuronal excitability pathways. Together, these findings define an adipose-complement-lipid axis that regulates nociceptive vulnerability independent of joint damage and identify extra-articular targets for translational, non-opioid OA pain therapies. One Sentence SummaryWe identify an adipose-complement-lipid axis that systemically regulates sensory neuron sensitization, providing a mechanistic basis for pain-structure discordance in obesity-associated osteoarthritis.

physiology↗

bioRxiv2025

Complement factor D (adipsin) mediates pressure-pain hypersensitivity post destabilization of medial meniscus injury

BACKGROUNDAlthough osteoarthritis (OA) is the leading cause of pain and disability worldwide, there is a lack of models to probe the separable mechanism of OA structural damage and knee pain. We previously identified that deletion of complement factor D (FD) results in increased pressure-pain hyperalgesia despite cartilage protection after destabilization of the medial meniscus (DMM) surgery. However, how these discordant OA phenotypes manifest is not understood. We employed a novel targeted lipidomics approach to elucidate the role of eicosanoids in FD-mediated pain. We hypothesize that the absence of Cfd (FD-/-) will protect cartilage but cause increased pressure-pain hyperalgesia and eicosanoid dysregulation that persists throughout OA development. METHODSMale and female FD-/- and wild-type (WT) mice were challenged with DMM or remained naive (n=5-11/group) at 16 weeks old. Pressure-pain hyperalgesia was measured bi-weekly for 8 weeks post-DMM. A second cohort was evaluated at 2 weeks post-DMM (n=6-10/group) to investigate DMM injury response. Structural damage was scored using the Modified Mankin system. To determine changes in eicosanoid profiles, serum and synovial fluid samples were analyzed via liquid chromatography-mass spectrometry (LC-MS). Statistical analysis was performed with unpaired t-test, two-way, or three-way ANOVA with Sidaks posthoc test. Statistical significance is defined as p<0.05. RESULTSIn contrast to WT mice, FD-/- showed no significant differences in Modified Mankin scores 8 weeks post-DMM. As expected, FD-/- hyperalgesia levels persisted until 8 weeks post DMM, similar to WT. Changes in eicosanoid profiles of pain-associated factors in FD-/-when compared to WT were found in the synovial fluid at 2 weeks and the serum at 8 weeks post-DMM. CONCLUSIONThe absence of Cfd drives knee hyperalgesia in male and female mice at 2 weeks-post DMM and persists through an 8-week observation period despite observing cartilage protection. Changes of eicosanoid profiles at both time points suggest that FD drives pain acutely, and the hyperalgesia phenotype emerges early in response to DMM injury, elucidating the role of the alternative complement in mediating OA pain and structural damage.

physiology↗

bioRxiv2025

Chondrocyte-Specific Knockout of Piezo1 and Piezo2 Protects Against Post-Traumatic Osteoarthritis Structural Damage and Pain in Mice

AbstractO_ST_ABSBackgroundC_ST_ABSOsteoarthritis (OA) is a debilitating joint disease characterized by cartilage degeneration, synovial inflammation, and bone remodeling, with limited therapeutic options targeting the underlying pathophysiology. Mechanosensitive ion channels Piezo1 and Piezo2 play crucial roles in chondrocyte responses to mechanical stress, mediating mechanotransduction pathways that influence chondrocyte survival, matrix production, and inflammatory signaling, but their distinct contributions to OA pathogenesis remain unclear. MethodsUsing inducible, chondrocyte-specific Aggrecan-Cre (Acan) mice, we investigated Piezo1, Piezo2, and combined Piezo1/2 conditional knockouts (cKOs) using the destabilization of the medial meniscus (DMM) model of post-traumatic OA in male and female mice. Pain and behavioral assessments were conducted at four time points to evaluate OA progression, while cartilage damage, bone remodeling, and synovial inflammation were assessed at the final endpoint of 28 weeks. Statistical analyses included one-way and two-way ANOVA with Tukeys multiple comparisons test. ResultsPiezo1 cKO delayed pain onset but ultimately exacerbated cartilage degradation and synovitis, emphasizing its dual role in protective and pathogenic mechanotransduction. While the Piezo2 cKO reduced pain and preserved activity, it failed to protect cartilage. Notably, Piezo1/2 cKO provided the greatest protection against cartilage degeneration, synovitis, and pain. Micro-computed tomography analyses revealed that Piezo2 is critical for maintaining trabecular bone integrity, with a Piezo2 cKO leading to decreased bone volume, thickness, and density, independent of injury. Piezo2 cKO also reduced normal meniscal ossification that occurs with age in mice. In contrast, a Piezo1/2 cKO normalized most bone remodeling parameters observed in Piezo2 cKO mice but did not restore medial tibial plateau thickness, highlighting Piezo2s essential role in bone structure. ConclusionsThese findings demonstrate the overlapping and compensatory roles of Piezo1 and Piezo2 in OA pathogenesis. Dual inhibition of Piezo1 and Piezo2 may offer a novel, effective therapeutic strategy targeting both structural and symptomatic aspects of the disease.

physiology↗

bioRxiv2020

Adipose Tissue is a Critical Regulator of Osteoarthritis

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects obese individuals. The mechanisms by which adipose tissue leads to the onset and progression of OA are unclear due to the complex interactions between the metabolic, biomechanical, and inflammatory factors that accompany obesity. We used a murine model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or post-traumatic OA, on either a chow and high fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to post-traumatic OA was reintroduced into LD mice using implantation of adipose tissue derived from wildtype animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a critical mediator of joint degeneration.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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