Open Access

NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis

Arthritis Research & Therapy201315:119

DOI: 10.1186/ar4320

Published: 30 September 2013


Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized bysynovial membrane hyperplasia, inflammation, and angiogenesis. Hepatocyte growthfactor (HGF) and its receptor, c-Met, are both overexpressed in the RA synovium.NK4 is an antagonist of HGF which has been shown to inhibit tumor growth,metastasis, and angiogenesis. In an experimental model of RA, NK4 gene therapyinhibited joint damage and inflammation in both preventative and therapeuticmodels. NK4 treatment therefore represents a possible therapeutic option incombating RA.

Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune diseasecharacterized by an erosive synovitis. In addition to being an inflammatorycondition, RA is also considered to be a member of the angiogenic family ofdiseases. Angiogenesis is growth of new blood vessels from pre-existing bloodvessels. As the disease progresses, the hyperplastic synovial pannus creates ahypoxic, inflammatory environment that induces angiogenesis. Further vascularizationof the synovial tissue promotes pannus growth and continued infiltration ofinflammatory leukocytes, thus perpetuating the disease.

In the previous issue of Arthritis Research & Therapy, Tsunemi andcolleagues [1] reported on the targeting of hepatocyte growth factor (HGF) by NK4 in thetreatment of RA. HGF is a pleiotropic growth factor that is expressed by mesenchymalcells and promotes processes such as mitogenesis, differentiation, and angiogenesis [2]. It mediates these functions via binding to its unique receptor c-Met, areceptor tyrosine kinase. c-Met is expressed by a variety of cell types, includingendothelial cells (ECs) [3].

We have previously shown that HGF is elevated in the synovial fluid of patients withRA [4]. More recently, Grandaunet and colleagues [5] found that plasma levels of HGF predict the severity of joint damage inpatients with RA. In the joint, we found that HGF and c-Met are elevated in the RAsynovial lining compared with normal controls [4]. The report by Tsunemi and colleagues [1] supports these findings and further shows that c-Met is expressed onfibroblasts, mononuclear cells, and ECs in the RA synovium.

HGF is a heterodimeric protein composed of an ?-chain, which contains four kringledomains, and a ?-chain [6]. The ?-chain binds c-Met with high affinity, whereas the ?-chain isresponsible for activation of c-Met. In an attempt to inhibit HGF, Date andcolleagues [7] generated a cleavage product of HGF termed NK4, which contains the fourkringle domains of the HGF ?-chain. Therefore, NK4 serves as an antagonist of HGFand can bind c-Met with high affinity without activating it.

As described above, one of the primary functions of HGF is to induce angiogenesis bybinding to c-Met on the surface of ECs. Therefore, it was postulated that NK4 wouldact as a competitive inhibitor of HGF, thus inhibiting angiogenesis. Indeed, NK4 hasbeen shown to inhibit angiogenesis in vitro and in various in vivocancer models [6, 8, 9]. However, in addition to having antagonistic action against HGF, NK4inhibits angiogenesis induced by vascular endothelial growth factor and basicfibroblast growth factor in a c-Met-independent fashion [9]. In addition to c-Met, NK4 binds to perlecan, a sulfate proteoglycan thatinteracts with the vascular endothelial basement membrane. Sakai and colleagues [9] found, specifically, that NK4 binds perlecan and prevents properfibronectin assembly in the basement membrane, which inhibits several facets ofangiogenesis.

These features of NK4 make it an attractive potential adjunctive therapy inangiogenic diseases. Over the past decade, numerous studies have been performed toassess the efficacy of either a recombinant NK4 protein or NK4 gene expressionvector in many experimental cancer models [3, 6]. Collectively, these studies have indicated that NK4 treatment has thepotential to inhibit tumor growth, angiogenesis, and metastasis [3, 6]. Much of the preclinical success of NK4 can be attributed to its abilityto inhibit multiple pathways involved in growth and angiogenesis.

RA is driven by inflammation and angiogenesis, and thus much work has been aimed atidentifying and testing potential angiogenesis inhibitors in models of experimentalarthritis [10]. Tsunemi and colleagues [1] have now adopted their approach of studying the antiangiogenic propertiesof NK4 in cancer to experimental arthritis. Using an adenovirus vector containingthe NK4 gene, they found that NK4 inhibited the development of ?-glucan-inducedarthritis [1]. NK4 was able to inhibit inflammation, joint swelling, and bone erosion.However, the authors did not show direct evidence of NK4 inhibiting synovial bloodvessel density. Importantly, they also showed that NK4 gene therapy was effectivewhen given therapeutically, after the onset of the experimental arthritis [1].

These results are highly encouraging in the application of NK4 as a potentialadjunctive RA therapy. This report, coupled with the high expression levels of HGFand c-Met in the RA synovium, makes NK4 treatment an intriguing possibility. In thefuture, it will be of great interest to determine whether these effects of NK4 areobservable in other animal models of RA, as not all facets of RA are represented ina singular model of the disease. Moreover, many of the effects of NK4 observed byTsunemi and colleagues [1] are attributed to a reduction in inflammation and inflammatory cytokines.Therefore, elucidating the anti-inflammatory and antiangiogenic mechanisms of NK4will be paramount to transitioning from an interesting candidate to a possible RAtherapy.



Endothelial cell


Hepatocyte growth factor


Rheumatoid arthritis.


Authors’ Affiliations

Department of Biology
Department of Internal Medicine, University of Michigan Medical School


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