Efficacy of simultaneous blockade of myostatin and activin on the inhibition of joint destruction in experimental arthritis

• Applicant: Berno Dankbar, Ph.D.
• Subject Area: Rheumatology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515320408

Rheumatoid arthritis (RA) is the prototype of an inflammatory arthritis that is characterized by chronic inflammation, synovial hyperplasia, progressive cartilage destruction and bone erosion. In a recently published work, we described that chronic inflammation leads to an upregulation of myostatin in arthritic synovial tissues and that deficiency or pharmacological inhibition of myostatin highly ameliorates disease severity and in particular bone erosion and pannus formation in arthritic mice. Additionally, we could recently show that like myostatin, another member of the TGF-ß family namely activin A stimulates RANKL-induced osteoclast differentiation and inhibits osteoblast differentiation. Moreover, deficiency of activin A leads to decreased inflammation and bone destruction. Altogether, both myostatin and activin appear to be key players in arthritis development and associated joint destruction.Therefore, inhibiting myostatin and activin A simultaneously, thereby blocking not only osteoclast development, macrophage activation and fibroblast (FLS) proliferation but also promoting bone formation, may provide a powerful tool for the treatment of joint destruction in RA.In this context, a protein which is able to bind and antagonize myostatin as well as activin is the natural occuring antagonist follistatin (FST) and indeed a recombinant modified FST (FSTΔHBS-mFc) has been shown to have the capability to effectively block myostatin as well as activin signaling. Moreover, besides blocking myostatin and activin directly, inhibition could also be achieved by targeting the corresponding receptors thereby inhibiting receptor-ligand binding. In line with this, a dual-specific antibody against Acvr2a/ Acvr2b has been shown to facilitate a complete blockade of the myostatin- or activin A signaling response.Taking the inhibitory properties of FSTΔHBS-mFc and anti-Acvr2a/2b antibody into account, we want to test the efficacy of these factors to ameliorate inflammatory joint destruction in various mouse models of RA. In the present project, we proposed to study and compare the effects of FSTΔHBS and the dual-specific anti-Acvr2a/b antibody on cartilage and bone erosion, pannus formation, cytokine and chemokine production and immune cell infiltration in a chronic (hTNFtg) as well as an acute (K/BxN serum transfer) arthritis model.Moreover, investigating the impact of both inhibitors as well as FLS-expressed FST on osteoclast and osteoblast differentiation and on FLS aggressive behavior itself is focus of our in vitro studies. In this regard, conditioned media experiments with arthritic FLS, osteoblasts and BMMs will provide insights into the impact of paracrine myostatin/ activin on osteoclast and osteoblast development. Functional assays on FLS adhesion, proliferation, migration and invasion should provide detailed information about the effectiveness of simultaneous inhibition on pannus formation and cartilage degradation by activated FLS.

• DFG Programme: Research Grants
• International Connection: Denmark
• Cooperation Partner: Andreas Lodberg, Ph.D.