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Homeostasis and repair are critical biological processes that allow for tissue and organ preservation and function in multicellular organisms. Their regulation and extension vary drastically across the animal kingdom, and mammals show limited tissue-specific regenerative capacity that declines with age. During aging, articular cartilage is one of the tissues that undergo substantial changes in the matrix structure, molecular composition, metabolic activity, and mechanical properties (Loeser et al. 2016). As a result, articular cartilage experiences impaired homeostasis and limited capacity to undergo repair, contributing to osteoarthritis (OA) development (Loeser et al. 2016). OA is the most prevalent musculoskeletal disorder among the elderly and is the leading cause of disability in the US due to pain associated with the disease (Zhang et al. 2016). Although symptomatic pain relief is possible (Zhang et al. 2016), treatments to cure the pathology are currently unavailable. Interestingly, contrary to the loss of homeostasis and repair capacity with age, during embryogenesis as well as a short period after birth, mammals seem to have a higher regeneration capacity (Vivien et al. 2016). These and other facts beg the question of whether therapeutic targets can be developed towards the enhancement of the low regenerative capacity observed during adulthood and worsen upon aging. We thus focused our attention on two molecules, αKLOTHO and soluble Transforming growth factor-beta receptor 2 (sTGFβR2), that have been individually described in cartilage homeostasis. The inhibition of the transforming growth factor β isoform 1 (TGFβ1) appears to inhibit osteophyte formation despite increasing proteoglycans degradation (Scharstuhl et al. 2002), whereas αKLOTHO seems to act as an important inhibitor of extracellular matrix (ECM) degradation (Chuchana et al. 2018). Although TGFβ1 was considered as a reparative mediator by stimulating chondrocyte proliferation and inhibiting chondrocyte hypertrophy (VarelaEirin et al. 2018), recent findings also provide substantial evidence about the contribution of TGF-β/Smad signaling in OA development and progression. Maintaining a balance in the TGFβ1 pathway appears to be key in regulating cartilage homeostasis, either the increase of activin receptor-like kinase (ALK) ALK1/ALK5 receptors ratio (Varela-Eirin et al. 2018) or a prolonged exposure to TGFβ1 have been demonstrated to boost chondrocyte hypertrophy (Bakker et al. 2001). In fact, the study of TGFβ1 levels in the knee joint of human patients suggests that active TGFβ levels are very low or absent in healthy articular joints, while drastically elevate in joint diseases such as OA (Scharstuhl et al. 2002). sTGFβR2, which lacks the membrane-binding domain and shows a higher affinity for TGFβ1 and β3 (De Crescenzo et al. 2003), can be used to modulate TGF-β pathway. The other molecule, αKLOTHO, was initially identified as an antiaging molecule in mice and shown to be downregulated in the cartilage and synovial membrane upon aging and OA (Pásztói et al. 2009). Although its specific role in articular cartilage is still unknown, αKLOTHO seems to prevent apoptosis, oxidative stress, and immune reaction in other organs (Hu and Moe 2012), all pathways known to be involved in OA development. We then hypothesized that combining both the molecules could enhance the regenerative capacity to restore the articular cartilage structure and function after OA. First, OA was chemically induced in rats by intra-articular injection of papain. This enzyme does not impact the chondrocytes; so, it would not impair the regeneration mechanism of the cartilage. We analyzed the rat knee joints four weeks after the papain injection by comparing the osteoarthritis control group (here on, OAC) and a healthy control group of rats (here on, HC) (Fig. S1). The Safranin-O staining of the OAC group showed diminished cartilage thickness with discontinued fibrillar surface and cellular clusters within the cartilage (Fig. S1A and S1B). Clear signs of early-stages of OA were found four weeks after papain treatment, according to the normalized Osteoarthritis Research Society International (OARSI) scores (see Supplementary Materials). The OAC group showed a clear grade 2 OA (Fig. S1C) as defined by the parameters analyzed. The OA grade in these samples was further supported by the increase in the number of cells undergoing apoptosis detected by tunel staining (Fig. S1D). Moreover, compared to the HC group, OAC group shows an increased area of expression of collagen

αKLOTHO and sTGFβR2 treatment counteract the osteoarthritic phenotype developed in a rat model