Since the prominent Alizarin red staining of neo-osseous tissue, concurrent with DIO2 upregulation could explain the extensive phenotypic foci of calcified cartilage observed in affected articular cartilage tissue of CCAL1 family members, we hypothesize that the chondrocalcinosis observed in OPG-XL carriers is likely not preceding OA onset in cartilage but arises merely during ongoing OA pathophysiology, i.e. when chondrocytes have a tendency to undergo trans-differentiation to osteoblasts [33]. This evidence concerns the gene TNFRSF11B and chondrocalcinosis.