About

Carla R. Scanzello, MD, PhD, is an Associate Professor of Medicine (Rheumatology) at the Hospital of the University of Pennsylvania and a member of several institutes within the Perelman School of Medicine, including the Institute for Immunology & Immune Health, the Institute for Translational Medicine and Therapeutics, and the Penn Center for Musculoskeletal Disorders. Her research focuses on understanding the molecular stimuli and clinical consequences of synovial inflammation in osteoarthritis (OA) and meniscal injury. She has identified specific inflammatory pathways, such as Toll-like receptor pathways and chemokine-mediated pathways, that are over-expressed in patients with early-stage knee OA. Her work explores how these pathways influence OA development and progression after joint injury using animal models, with an emphasis on pain-related outcomes and translational relevance. The ultimate goal of her laboratory's work is to develop novel anti-inflammatory strategies to reduce pain and disability from OA.

Research topics

• Medicine
• Pathology
• Immunology
• Internal medicine
• Physical therapy

Selected publications

• CD14-deficiency protects against osteoarthritic subchondral bone sclerosis via enhanced osteoclastogenesis following joint injury

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-11

  articleOpen accessSenior authorCorresponding

  Abstract Aberrant bone remodeling is a hallmark of osteoarthritis, the most common arthritis affecting over 27 million US adults. Subchondral bone sclerosis, one sign of aberrant bone remodeling observable by routine x-rays, occurs as the trabeculae thicken, leading to increased bone volume. Toll-like receptors, pattern-recognition receptors of the innate immune system, have been implicated in OA pathogenesis, with TLR ligands, receptors, and co-receptors shown to mediate the severity and progression of OA. We have previously shown that CD14-deficiency protects mice against post-traumatic OA, and specifically reduces subchondral sclerosis post-injury. We hypothesized that depletion of CD14 protects against TLR4-dependent inhibition of osteoclastogenesis and therefore increases OC density in the SCB after injury, mitigating aberrant bone deposition in a murine model of OA . To determine how cellular changes correlate with bone structure derangements post-DMM, we performed MicroCT, Tartrate-resistant acid phosphatase staining, and alkaline phosphatase staining. To establish mechanistic changes in cellular signaling, we isolated WT and CD14-deficient osteoclast precursors and subjected them to LPS, an osteoarthritis-relevant TLR ligand, during differentiation. CD14-deficient mice, as well as WT mice treated with an anti-CD14 monoclonal antibody, show protection from post-injury increases in both bone volume fraction and bone mineral density. CD14-deficient mice had an increased osteoclast presence in the SCB two weeks post-injury, potentially protecting them from increases in bone volume and density. In vitro , CD14-deficient OCPs differentiated faster than WT OCPs, due to reduced Type I Interferon (IFN-I) signaling. In the presence of an LPS challenge, CD14-deficient OCPs were protected against LPS and TLR4-mediated inhibition, likely due to decreased MyD88-dependent TLR4 signaling. This work opens up new potential pathways to therapeutically target aberrant bone remodeling in the setting of joint injury and PTOA. Lay Summary Osteoarthritis is one of the leading causes of disability worldwide. One of the hallmarks is subchondral sclerosis, or thickening of the bone in and around the joint. In this work, we used a mouse model of osteoarthritis to show that decreasing inflammatory signaling, through removal of CD14, protects against subchondral sclerosis, due to an increased presence of osteoclasts, cells that combat bone thickening. Osteoclasts without CD14 differentiate faster than osteoclasts with CD14, due to decreased Type I Interferon, an inflammatory cytokine. Graphical Abstract

  PublisherOA PDFDOI

• Sustained Structural and Functional Deficits in the Porcine Knee Six Months Following Meniscus Destabilization

  Journal of Orthopaedic Research® · 2026-01-01 · 1 citations

  articleOpen access

  Osteoarthritis (OA) of the knee is a leading cause of pain and disability. Large animal models that accurately reflect the human OA phenotype are essential for evaluating new therapeutics. This study sought to evaluate a porcine model of knee injury using an enhanced destabilization of the medial meniscus (DMM+) approach in which a 5 mm portion of the medial meniscus anterior (cranial) attachment (cranial medial meniscotibial ligament) was resected. A series of quantitative and semi-quantitative measures of joint-wide structure and function were used to assess joint degeneration at 6 weeks and 6 months postoperatively, including cartilage mechanical testing, subchondral bone analysis, osteochondral and synovial histology and gait analysis. Results showed that early degenerative changes were localized to regions experiencing a change in mechanical loading, with changes including decreased cartilage mechanics and subchondral bone sclerosis. By 6 months, despite resolution of the subchondral bone changes, other features of degeneration became more diffuse, with cartilage softening, synovial inflammation, and altered gait being apparent at this time point, indicating a transition from acute mechanical insult to chronic joint pathology. This large animal model results in OA-like changes to cartilage mechanics and synovium, mimicking some key aspects of human OA, making it a potentially valuable platform in which to test disease-modifying treatments and regenerative strategies.

  PublisherOA PDFDOI

• Intra-articular Delivery of Recombinant Interleukin-1 Receptor Antagonist Protein (Anakinra) Enhances Graft Function in a Porcine Model of Osteochondral Repair

  The American Journal of Sports Medicine · 2026-01-21

  articleOpen access

  BACKGROUND: Osteochondral autografts may be subject to suboptimal healing and graft degeneration due to surgical insult and the inflammatory environment of an injured joint. PURPOSE/HYPOTHESIS: The purpose of this study was to alleviate the negative effect of this inflammatory milieu on the healing of osteochondral grafts by treating operative joints with interleukin-1 receptor antagonist (IL-1ra; Anakinra) in a porcine model. It was hypothesized that such treatment would reduce markers of inflammation and lead to improved implant structural and functional outcomes. STUDY DESIGN: Controlled laboratory study. METHODS: The authors performed an osteochondral autograft transfer (OAT) procedure on the weightbearing surface of the medial femoral condyle of adult Yucatan minipigs. Beginning 1 week after surgery, a subset of animals received an intra-articular injection of 8 mg Anakinra in the operative stifle on a weekly basis for 4 weeks. At the 5-week endpoint, mechanical testing of the cartilage was performed, synovium and osteochondral specimens were analyzed histologically using semiquantitative scoring systems, and subchondral bone was analyzed via micro-computed tomography. RESULTS: IL-1ra-treated joints showed significantly less histological evidence of synovial inflammation. Autografts from treated joints showed better retention of mechanical properties and better histological scores. CONCLUSION: Results indicate that intra-articular IL-1ra administration after surgery significantly improves graft structure and function and dramatically enhances healing. CLINICAL RELEVANCE: This study demonstrates that local provision of adjuvant anti-inflammatory therapeutics after OAT may enhance healing and protect graft integrity. This not only has implications for current clinical practice of osteochondral autograft (and allograft) procedures but also may allow expanded indications for advanced biological repair in a greater number of patients.

  PublisherDOI

• Mechano-activation of synovial fibroblasts and macrophages during OA progression in the dynamically stiffening synovial microenvironment

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-18 · 1 citations

  articleOpen accessSenior authorCorresponding

  Abstract Objective During osteoarthritis (OA) progression, the synovial membrane undergoes profound structural and compositional remodeling and fibrosis. We sought to elucidate how evolving synovial microenvironmental mechanics during fibrotic remodeling influence cell behavior and drive the progression of synovial pathology. Methods Skeletally-mature male C57BL/6J mice were subjected to destabilization of the medial meniscus (DMM). To control for surgical confounders, both sham-operated and unoperated mice were included, with evaluation at 4– and 8-weeks. Synovial micromechanics were quantified via atomic force microscopy (AFM). Single-cell RNA sequencing (scRNA-seq), RNA fluorescence in situ hybridization (FISH), and flow cytometry were employed to investigate cellular heterogeneity, spatial organization, and crosstalk within fibrotic and non-fibrotic synovial niches. Results Progressive fibrotic remodeling and marked matrix stiffening were observed in DMM-operated synovium but absent in sham– and un-operated controls. While both sham and DMM joints mounted an acute stromal and immune response to surgery, these changes resolved over time in sham conditions but persisted in DMM synovium. During disease progression, distinct functional subsets of synovial fibroblasts and immune cells emerged, with mechanosignalling pathways and distinct immune cell-fibroblast crosstalk robustly activated within DMM-induced fibrotic microenvironments. Conclusion This study demonstrates the complex cellular dynamics and crosstalk that differentiate the evolution of the pathological synovial response in the fibrotic DMM condition relative to surgical sham controls. Our findings highlight mechanotransduction as a central mechanism driving OA synovial pathogenesis and underscore the utility of the DMM model as a platform to dissect the molecular underpinnings of synovial fibrosis.

  PublisherOA PDFDOI

• Cellular and molecular mechanisms underlying subchondral bone remodeling and associated pain in osteoarthritis

  Connective Tissue Research · 2025-08-13 · 1 citations

  reviewSenior author

  Osteoarthritis (OA) is the most common musculoskeletal-related disease affecting over 27 million US adults, and no disease-modifying agents are currently available. Signs of bone remodeling are a major hallmark of OA, and include subchondral sclerosis (seen on x-ray), subchondral bone marrow lesions (seen on MRI), and osteophytosis. Recent work suggests subchondral bone remodeling is likely a driver of pain in OA. In this review, we seek to provide an overview on what is known about the cellular and molecular mechanisms that play a role in osteoarthritic subchondral bone remodeling and associated pain. Searching for "subchondral bone remodeling" "pain" and "osteoarthritis," we reviewed publications from 2015 onward. We found new details of how osteoblasts, osteoclasts, and osteocytes communicate in both autocrine and paracrine manners in OA, allowing identification of potential candidates that play a role in the aberrant bone remodeling seen in OA. Furthermore, there is new knowledge regarding mechanisms of how bone cells communicate with nociceptive neurons, providing potential candidates to target for treatment of OA pain. Recent clinical trials targeting OA-associated bone remodeling have been published with some encouraging results. In the future, more work is necessary to understand the inciting events that lead to the pathogenic cell behaviors, and unravel the complex cellular communication detailed in this review. In addition, efforts to understand the discordant results from recent trials of existing agents targeting bone remodeling and to develop novel bone-targeted agents for OA are needed.

  PublisherDOI

• Imaging Mass Cytometry Reveals Distinct Early Changes in the Synovial Cellular Landscape in Overloading and Surgical OA Models

  Osteoarthritis and Cartilage · 2025-04-01

  articleSenior author
  PublisherDOI

• Multi-Model Evaluation of the Impact of CD14 on Synovial Inflammation & Pain During PTOA

  Osteoarthritis and Cartilage · 2025-04-01

  articleSenior author
  PublisherDOI

• Synovial changes in osteoarthritis: symptom or disease driver?

  Connective Tissue Research · 2025-09-03 · 2 citations

  article

  Osteoarthritis (OA), long regarded as simply a disease of articular cartilage degeneration, has increasingly been recognized as a complex disorder involving multiple joint tissues, including the synovium. This review explores the emerging evidence that synovial changes seen in OA are not merely secondary to cartilage breakdown but may actively drive OA progression. We detail the physiological role of the synovium in joint homeostasis and highlight pathological remodeling processes, such as synovial hyperplasia, immune cell infiltration, and fibroblast activation, that contribute to joint degeneration. Mechanistic insights implicate fibroblast-like synoviocytes and synovial macrophages in initiating and perpetuating inflammatory and catabolic cascades that alter synovial fluid composition, impair cartilage integrity, and exacerbate disease symptoms. Clinical and preclinical data increasingly link synovitis and synovial damage to structural disease progression and pain, underscoring their prognostic and therapeutic significance. Despite promising targets, effective disease-modifying therapies remain elusive due to the molecular complexity and clinical heterogeneity of the disease and limitations in early diagnostic evaluations. To overcome this, innovative research methods, improved diagnostic tools, and interdisciplinary collaboration will be critical. Collectively, this work advocates for a paradigm shift that the synovium is a central player in OA pathogenesis and a viable target for therapeutic intervention.

  PublisherDOI

• NERVE GROWTH FACTOR IS SUFFICIENT TO CAUSE MULTIPLE OSTEOARTHRITIS-RELEVANT PATHOLOGICAL FEATURES IN NAÏVE MURINE KNEE JOINTS

  Arthritis & Rheumatology · 2025-06-26

  preprintOpen access

  ABSTRACT BACKGROUND Nerve growth factor (NGF), a key mediator of pain and inflammation, is increased in joints with osteoarthritis (OA). Neutralizing NGF with monoclonal antibodies has shown analgesic effects in painful knee OA, but clinical development was stopped due to side effects in the joints. Knowledge about the biological effects of long-term exposure of joint tissues to NGF is limited. Therefore, we aimed to explore the effects of repeated intra-articular (IA) injections of NGF into the knee joints of healthy mice on pain and sensitization, as well as joint innervation and structure. METHODS We conducted five experiments in male C57BL/6 mice. In Experiment 1, NGF (50ng or 500ng) or vehicle was injected IA into the knee of naive wildtype (WT) mice, twice a week for 4 weeks. We assessed knee swelling, knee hyperalgesia and histopathology. In Experiment 2, mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks and microCT of the knee was performed. In Experiment 3, Na V 1.8-tdTomato reporter mice were injected with 500ng NGF or vehicle, twice a week for 4 weeks, and joint innervation was assessed. In Experiment 4, WT mice received 500ng NGF or vehicle twice a week for 4 weeks and were used for single cell RNA sequencing (scRNAseq) of the synovium. In Experiment 5, L3-L5 DRGs of mice that received 3 IA injections of 500ng NGF or vehicle twice a week were used for bulk RNA sequencing. RESULTS Repeated bi-weekly IA injections of NGF caused knee hyperalgesia in naïve mice. NGF caused dose-dependent knee swelling, synovial pathology, increased bone mineral density and trabecular bone thickness in the medial subchondral bone, growth of pre-osteophytes in the medial compartment, but no cartilage degeneration. NGF injection caused sprouting of Na V 1.8+ neurons in the medial but not the lateral synovium. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis and ossification, confirming histopathological findings. Bulk RNA seq of DRG showed upregulated pathways related to axonal growth. CONCLUSIONS In healthy mouse knees, NGF induced mechanical sensitization, synovitis, neoinnervation in the medial synovium, subchondral bone changes and pre-osteophyte growth in the medial compartment, thus capturing many pathological changes observed in OA, except cartilage damage.

  PublisherDOI

• Synovial fibroblasts support vascular function in an acute injury-on-a-chip model

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-17

  preprintOpen access

  Abstract Most patients who sustain an acute joint injury develop degenerative joint disease, or osteoarthritis (OA). Animal models have informed the design of OA therapeutics; however, no disease-modifying therapy has successfully translated to human patients. Thus, there is a strong motivation to develop humanized in vitro platforms to fill a critical gap in knowledge of disease progression post-injury. Here, we develop an acute injury-on-a-chip model of the synovium, a vascularized, joint-lining tissue that has been implicated in OA progression and as a key driver of joint disease. We apply this chip-based system to investigate crosstalk between endothelial cells, lining an engineered vessel, and synovial fibroblasts, embedded within an extracellular matrix hydrogel. Our data indicate that synovial fibroblasts, rather than initiating disease, attempt to support and maintain vascular function in the presence of acute inflammation (i.e., interleukin-1β). Such knowledge may provide new targets for OA therapeutics, preventing the progression from joint injury to disease in patients. Teaser In the presence of inflammation, a hallmark of acute injury, synovial fibroblasts work to maintain vascular health.

  PublisherDOI

Recent grants

• CCR7 and its ligands in Osteoarthritis

  NIH · $387k · 2015–2018

• Modulation of Inflammation in Osteoarthritis via CD14-mediated pattern recognition

  NIH · $2.1M · 2020–2026

• The Impact of C-C Chemokine Receptor 7 (CCR7) on Synovitis and Osteoarthritis (OA)

  NIH · 2015–2019

• NIH Grant K08AR057859

  NIH · $620k · 2016

Frequent coauthors

• Rui Xiao

  Nanchang University

  90 shared

• Joshua F. Baker

  Hospital of the University of Pennsylvania

  90 shared

• Tuhina Neogi

  Boston University

  89 shared

• Bryant R. England

  VA Nebraska Western Iowa Health Care System

  87 shared

• Katherine D. Wysham

  University of Washington

  87 shared

• Daniel K. White

  University of Delaware

  86 shared

• Alexis Ogdie

  85 shared

• Mercedes Quinones

  Washington DC VA Medical Center

  84 shared