Cartilage

Cartilage is an avascular tissue characterized by cartilage cells surrounded by an extracellular matrix consisting primarily of type II collagen and proteoglycans with sulfated glycosaminoglycan side chains assembled into large aggregates. It is found in a number of anatomic locations, with modifications to meet the specific requirements for its function. Cartilage development is regulated by vitamin D metabolites, including 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃) and 24R,25-dihydroxyvitamin D₃ (24R,25(OH)₂D₃). In the postfetal growth plate, 1α,25(OH)₂D₃ acts via the vitamin D receptor (VDR) to control chondrocyte maturation, tether formation, matrix metalloproteinase activity, and release of Ca⁺⁺ into the extracellular matrix for calcification. VDR-null mice, which lack a functional VDR, develop an elongated hypertrophic cell zone, characteristic of rickets, demonstrating the importance of the VDR in growth plate maturation and calcification. In addition to traditional nuclear VDR-dependent signaling mechanisms, 1α,25(OH)₂D₃ acts through nongenomic mechanisms mediated by protein disulfide isomerase family A, member 3 to control phospholipase A₂, phospholipase C, protein kinase C, and mitogen-activated protein kinase signaling, as well as by acting directly on extracellular matrix vesicles, releasing matrix proteases, and activating transforming growth factor beta stored in the matrix. The importance of 1α,25(OH)₂D₃ to growth plate maturation, calcification, and subsequent resorption by osteoclasts has been demonstrated by studies using mice in which Cyp27B1 has either been knocked out or using transgenic mice in which Cyp27B1 is overexpressed. 24R,25(OH)₂D₃ acts via phospholipase D and lysophosphatidic acid signaling to promote cell survival, inhibit apoptosis, and reduce inflammatory cytokine production. The relative contributions of these two vitamin D metabolites help to determine the rate and extent of cartilage maturation, particularly in the growth plate during endochondral ossification, but also in articular cartilage.