Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

Abstract

Despite the knowledge that superficial zone chondrocytes (SZC, located within 100 μm of the articular surface) and deep zone chondrocytes (DZC, located near the calcified zone) have distinct phenotypes, previous studies on bone morphogenetic proteins (BMPs) have not differentiated its effects on SZC versus DZC. Using a pellet culture model we have compared phenotype, morphology and matrix accumulation in SZC and DZC with or without adenovirus-mediated overexpression of BMP-2 or -7 or the BMP antagonist Noggin. Greater accumulation of proteoglycan (PG)-rich matrix in the untreated DZC was associated with a hypertrophic phenotype with large cell diameters and high gene expression levels of runt-related transcription factor-2 (Runx2) as well as higher endogenous BMP activity. Noggin overexpression decreased matrix accumulation and cell diameters in SZC and DZC, confirming a role for endogenous BMP in both processes. In DZC, overexpression of either BMP2 or -7 increased cell diameter without increasing PG-rich matrix accumulation. In contrast, in SZC, BMP overexpression increased matrix accumulation and type II collagen gene expression without increasing cell diameter. These data indicate that differences in endogenous BMP activity level and responsiveness to BMPs define, in part, the differences between the SZC and DZC phenotype. They also suggest that SZC may be a more appropriate target for BMP therapy than DZC.

Enhanced nutrient transport improves the depth-dependent properties of tri-layered engineered cartilage constructs with zonal co-culture of chondrocytes and MSCs

“…Previous studies have shown that freshly isolated zonal chondrocytes (CHs) retained their zonal characteristics in 3D culture [8, 11]. Based on these findings, we fabricated a tri-layered construct [7] by partially polymerizing a zonal CH and MSC mixture in sequential layers of HA hydrogel (SZ-MSC, MZ-MSC and DZ-MSC, respectively) (Fig 1B).…”

“…These studies have shown that CHs from different depths retain their zonal characteristics through expansion and in 3D culture systems. For example, CHs isolated from deep zone cartilage produced more PG than those from the superficial zone [7–11]. Interestingly, when these zonal CHs were separately seeded into layered hydrogel constructs, zonal CHs established engineered constructs with some degree of depth dependence [7, 8, 11–15].…”

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis

“…Chondrocytes in the superficial zone express lubricin (also known as superficial zone protein or proteoglycan‐4), which plays an essential role in boundary lubrication. In addition, the expression of molecules such as parathyroid hormone‐related protein (PTHrP), Indian hedgehog (Ihh), and Runx2 may contribute to the zonal differences in matrix composition and function 3,4 . Chondrocytes exist at low oxygen tension, especially within the deep zones, and they may adapt to this environment in part by upregulating hypoxia‐inducible factor‐1α (HIF‐1α).…”

Distinct patterns of gene expression in the superficial, middle and deep zones of bovine articular cartilage

“…The gene expression of each articular cartilage zone is distinct. Additionally, the gene expression of each articular cartilage zone responds differentially to exogenous growth factor stimuli, including IGF‐1, bone morphogenetic proteins (BMPs), transforming growth factor‐ β 1 (TGF β 1), basic fibroblast growth factor (bFGF) and interleukin‐1 β (IL‐1 β ) (Cheng et al ., ; Coates and Fisher, ; Darling and Athanasiou, ; Eleswarapu et al ., ; Lee et al ., ; Leipzig et al ., ). Therefore, to gain a better understanding of the gene expression patterns of the superficial, middle and deep zones of hyaline articular cartilage, we have analysed the differential gene expression of each articular cartilage zone via genome array.…”