Chondrocyte Differentiation in Human Osteoarthritis: Expression of Osteocalcin in Normal and Osteoarthritic Cartilage and Bone

Abstract

Osteocalcin (OC), which is a marker of the mature osteoblasts, can also be found in posthypertrophic chondrocytes of the epiphyseal growth plate, but not in chondrocytes of the resting zone or in adult cartilage. In human osteoarthritis (OA), chondrocytes can differentiate to a hypertrophic phenotype characterized by type X collagen. The protein- and mRNA-expression pattern of OC was systematically analyzed in decalcified cartilage and bone sections and nondecalcified cartilage sections of human osteoarthritic knee joints with different stages of OA to investigate the differentiation of chondrocytes in OA. In severe OA, we found an enhanced expression of the OC mRNA in the subchondral bone plate, demonstrating an increased osteoblast activity. Interestingly, the OC protein and OC mRNA were also detected in osteoarthritic chondrocytes, whereas in chondrocytes of normal adult cartilage, both the protein staining and the specific mRNA signal were negative. The OC mRNA signal increased with the severity of OA and chondrocytes from the deep cartilage layer, and proliferating chondrocytes from clusters showed the strongest signal for OC mRNA. In this late stage of OA, chondrocytes also stained for alkaline phosphatase and type X collagen. Our results clearly show that the expression of OC in chondrocytes correlates with chondrocyte hypertrophy in OA. Although the factors including this phenotypic shift in OA are still unknown, it can be assumed that the altered microenvironment around osteoarthritic chondrocytes and systemic mediators could be potential inducers of this differentiation.

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

“…Regarding the treatment of articular cartilage defects, the engineered chondrocytes must arrest maturation processes, because abnormally matured hypertrophic chondrocytes, expressing COL10A1, mineralize cartilage matrix to cause pathological conditions such as osteoarthritis (OA) (22)(23)(24). This is a major problem of cartilage tissue engineering in an in vitro culture system, where MSCs rapidly express COL10A1 in a monolayer or pellet culture before the cells express hypertrophic phenotypes, suggesting that the mechanism by which MSCs induce type X collagen expression in vitro is different from that in chondrogenesis in vivo (25,26).…”

Correlation of Serum and Synovial Osteocalcin, Osteoprotegerin and Tumor Necrosis Factor-Alpha with the Disease Severity Score in Knee Osteoarthritis

“…Th is protein is a marker of bone formation and turnover. Its role in the pathology of osteoarthritis is still not fully known, but former studies reported an increased release of osteocalcin by subchondral bone [5][6][7].…”

The canonical Wnt signal paradoxically regulates osteoarthritis development through the endochondral ossification process

“…Recently, chondrocyte maturation has been implicated to be deeply involved in the pathogenesis of osteoarthritis. In articular cartilage of osteoarthritis patients, pathologic expression of type X collagen (COL10) and other differentiation markers, including annexin VI, alkaline phosphatase, osteopontin, and osteocalcin, have been reported, [16][17][18][19][20] indicating that the osteoarthritis articular cartilage cannot maintain the characteristics of the permanent cartilage, but adds those of the embryonic or growth plate cartilage. A mouse genetic study found the induction of Runx2, an essential transcription factor for chondrocyte hypertrophy, [21,22] in articular chondrocytes during osteoarthritis progression under mechanical stress, which led to cartilage degradation and osteophyte formation through the chondrocyte maturation and MMP production [23,24].…”