Significance: Obesity is a primary risk factor for osteoarthritis, involving complex interactions among the metabolic, biomechanical, and inflammatory factors caused by increased adiposity. Using a mouse model of lipodystrophy, we demonstrate that fat-free mice on either a chow or high-fat diet are protected from cartilage damage, despite demonstrating many factors previously associated with osteoarthritis. Furthermore, implantation of a small fat pad reverses cartilage protection in lipodystrophic mice, indicating a direct relationship between adipose tissue and cartilage damage, independent of body weight. This study provides evidence of adipose–cartilage signaling, indicating that tissues outside the joint can influence cartilage health. These findings support the notion that osteoarthritis involves a systemic component, providing insight into the development of new therapeutic targets for osteoarthritis.

Significance: Osteoarthritis is a common debilitating joint disease that affects millions in the United States and for which there are few therapeutic options. Critical barriers to the successful development of osteoarthritis treatment include limited understanding of the pathways governing early cartilage degradation and ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Using a peptidic nanoparticle carrying siRNA that specifically suppresses NF-κB, we show that early antiinflammatory intervention reduces chondrocyte death caused by joint injury, a known predisposing factor for osteoarthritis. The peptidic nanoparticle deeply penetrates human cartilage to deliver its therapeutic cargo to the chondrocytes, demonstrating its ability to permeate the dense cartilage matrix. This approach promises to overcome the barriers to effectively treat osteoarthritis.

Objective—: We previously established that neutrophil-derived dipeptidyl peptidase I (DPPI) is essential for experimental abdominal aortic aneurysm (AAA) development. Because DPPI activates several neutrophil serine proteases, it remains to be determined whether the AAA-promoting effect of DPPI is mediated by neutrophil serine proteases. Approach and Results—: Using an elastase-induced AAA model, we demonstrate that the absence of 2 neutrophil serine proteases, neutrophil elastase and proteinase-3, recapitulates the AAA-resistant phenotype of DPPI-deficient mice. DPPI and neutrophil serine proteases direct the in vitro and in vivo release of extracellular structures termed neutrophil extracellular traps (NETs). Administration of DNase1, which dismantles NETs, suppresses elastase-induced AAA in wild-type animals and in DPPI-deficient mice reconstituted with wild-type neutrophils. NETs also contain the cathelicidin-related antimicrobial peptide that complexes with self-DNA in recruiting plasmacytoid dendritic cells (pDCs), inducing type I interferons (IFNs) and promoting AAA in DPPI-deficient mice. Conversely, depletion of pDCs or blockade of type I IFNs suppresses experimental AAA. Moreover, we find an abundance of human cathelicidin peptide, a 37 amino acid sequence starting with 2 leucines and the human orthologue of cathelicidin-related antimicrobial peptide, in the vicinity of pDCs in human AAA tissues. Increased type I IFN mRNA expression is observed in human AAA tissues and circulating IFN-α is detected in ≈50% of the AAA sera examined. Conclusions—: These results suggest that neutrophil protease–mediated NET release contributes to elastase-induced AAA through pDC activation and type I IFN production. These findings increase our understanding of the pathways underlying AAA inflammatory responses and suggest that limiting NET, pDC, and type I IFN activities may suppress aneurysm progression.

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ∼50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various autoimmune and inflammatory human diseases.