Fetuin-A in post-traumatic osteoarthritis: at the crossroad between joint and muscle degeneration

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PROJECT ABSTRACT Joint damage caused by trauma can proceed to post-traumatic osteoarthritis (PTOA), with no cure available. Muscles are situated in joint proximity and are critical to absorb joint loads. Quadriceps weakness is one of the earliest findings in OA patients, can precede clinical OA, and is associated with increased pain. However, how muscle weakness relates to PTOA is unclear. In the efforts to identify OA treatments that can impact both tissue degeneration and pain, it is critical to identify novel factors acting on both joints and muscles. In this respect, fetuin-A represents an ideal candidate. Fetuin-A is a circulating glycoprotein synthesized in the liver and has been shown to have an anti-inflammatory role in injury, although its role in arthritis is still not clear. Decreased fetuin-A serum levels were shown to be correlated with more severe radiographic OA and pain. Fetuin-A is an antagonist of BMP signaling and regulates bone metabolism. Therefore, loss of BMP antagonism by reduced fetuin-A during OA, could allow for an unbalance in the local activity of BMPs, resulting in more chondrocyte hyperthrophy, and bone damage. A clinical study showed that sclerotic osteoblasts collected from late stage OA have significantly lower amounts of fetuin-A than non-sclerotic; our preliminary data in a mouse PTOA model (destabilization of medial meniscus, DMM) show that OA cartilage shows a drastic decrease of fetuin-A starting at the early stage OA and systemic fetuin-A administration in DMM mice reduced such damage. Importantly, it has been shown that BMP antagonism by Fetuin-A is also critical in muscle development and homeostasis. Our data in the DMM show that fetuin-A protein levels in quadriceps were decreased at both the mild and moderate OA stages; in addition, preliminary data in human OA muscles showed that protein fetuin-A levels were lower in OA quadriceps compared to controls. Taken together, these studies suggest that reduction in fetuin-A might play a key role in OA and its associated pain, affecting both joint and muscle tissues. We hypothesize that loss of fetuin-A after injury leads to cartilage and bone damage, along with muscle impairment, ultimately leading to PTOA and pain. By using the in-vivo DMM mouse post-traumatic OA model, we propose to determine whether fetuin-A, acting through BMP signaling, represents a therapeutic factor to preserve cartilage, bone and muscle integrity during OA and alleviate pain. Specifically, we will determine the fetuin-A protective effect during the DMM-induced OA by systemically overexpressing fetuin-A, as well as by local administration of fetuin-A intra- articularly using micro-particles for sustained slow release; we will follow cartilage/bone damage, inflammation and pain perception at different stages of PTOA (Aim1). Our new in-vivo preliminary data obtained by measuring the gastrocnemius soleus showed that muscle strength during DMM decreases starting at the moderate OA stage; therefore, in a separate set of experiments, we will use in-vivo and ex-vivo analyses of muscle function, to examine how systemic or intra-articular injected fetuin-A affect muscle strength during OA progression (Aim2). We will also determine fetuin-A downstream pathway changes in joint and muscle tissues.