Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn(2+)-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis.

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Pathological bone loss is caused by an imbalance between bone formation and resorption. The bone microenvironments are hypoxic, and hypoxia-inducible factor (HIF) is known to play notable roles in bone remodeling. However, the relevant functions of HIF-2α are not well understood. Here, we have shown that HIF-2α deficiency in mice enhances bone mass through its effects on the differentiation of osteoblasts and osteoclasts. In vitro analyses revealed that HIF-2α inhibits osteoblast differentiation by targeting Twist2 and stimulates RANKL-induced osteoclastogenesis via regulation of Traf6 . In addition, HIF-2α appears to contribute to the crosstalk between osteoblasts and osteoclasts by directly targeting RANKL in osteoprogenitor cells. Experiments performed with osteoblast- and osteoclast-specific conditional knockout mice supported a role of HIF-2α in this crosstalk. HIF-2α deficiency alleviated ovariectomy-induced bone loss in mice, and specific inhibition of HIF-2α with ZINC04179524 significantly blocked RANKL-mediated osteoclastogenesis. Collectively, our results suggest that HIF-2α functions as a catabolic regulator in bone remodeling, which is critical for the maintenance of bone homeostasis.

Osteoarthritis (OA) is characterized by impairment of the loadbearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho-Rho kinase-myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis. Various pathological conditions in human diseases are associated with aberrant ECM remodeling and consequent deviation from intrinsic ECM material properties (2). Mechanical perturbation of ECM affects the ways in which cells respond to externally applied mechanical forces and generate internal traction forces through cell-matrix interactions (3). Therefore, elucidation of the functional relationships between ECM mechanics and cellular transduction pathways is of critical importance.Articular cartilage ECM consisting of a collagenous network and highly charged proteoglycans confers the unique load-bearing function to joints. The dense aggregates of negatively charged proteoglycans provide resistance to compressive loading by promoting osmotic swelling, which is counterbalanced by cross-linked collagen fibrils that confer tissue tensile strength. Disruption of this delicate balance leads to structural damage and functional failure of articular cartilage and, consequently, to development of osteoarthritis (OA), the most common arthropathy (4, 5). OA cartilage ECM undergoes extensive remodeling, characterized by a decrease in matrix compliance (6, 7). These changes occur at the level of individual collagen fibrils, although the precise mechanisms regulating matrix remodeling remain elusive. Notably, matrix remodeling precedes cartilage destruction (6, 7), suggesting that monitoring the mechanical properties of cartilage matrix could serve as an innovative diagnostic approach for early detection of OA. Significant influence of matrix stiffness on mesenchymal lineage specification has been documented, and data have been obtained on the optimal ranges of substrate rigidity promoting osteogenesis. This regulatory process requires nonmuscle myosin II activity, with concomitant effects on adhesion and actin cytoskeleton structures (8).I...