Effects of Parathyroid Hormone (PTH) and PTH-Related Peptide on Expressions of Matrix Metalloproteinase- 2, -3, and -9 in Growth Plate Chondrocyte Cultures*

Abstract

The roles of PTH and PTH-related peptide (PTH-rp) in the expression of matrix metalloproteinases (MMPs) during endochondral bone formation were investigated, using various cartilages obtained from young rabbits and rabbit chondrocyte cultures. Immunohistochemical, immunoblotting, zymographical, and/or Northern blot analyses showed that MMP-2 and -9 levels were much higher in the growth plate than in permanent cartilage in vivo. In growth plate chondrocyte cultures, PTH, PTH-rp, and (Bu)2cAMP increased the amount of MMP-2 present in the culture medium, as revealed by zymograms and immunoblots, whereas the other tested growth factors or cytokines, including bone morphogenetic protein-2 and interleukin-1, did not increase the MMP-2 level. PTH also increased the MMP-2 messenger RNA level within 24 h. In addition, PTH increased MMP-3 and -9 levels in the growth plate chondrocyte cultures. However, in articular chondrocyte cultures, PTH had little effect on the levels of MMP-2, -3, and -9. In contrast to PTH, interleukin-1 induced MMP-3 and -9, but not MMP-2, in growth plate and articular chondrocytes. These findings suggest that in ossifying cartilage, PTH/PTH-rp plays a pivotal role in the induction of various MMPs, including MMP-2 (which is considered to be a constitutive enzyme), and that PTH/PTH-rp is involved in the control of cartilage-matrix degradation during endochondral bone formation.

Activation of Transforming Growth Factor β in Chondrocytes Undergoing Endochondral Ossification

“…The level of the 64‐kDa band remained essentially unchanged in each population throughout the culture period (Fig. 3A, lanes 1‐9), as seen previously (36, 38) …”

“…Several MMPs act to degrade the matrix during endochondral ossification and bone remodeling 33‐41) . The gelatinase MMP‐9 plays a role in degradation of the endochondral cartilage border, allowing for vascular invasion in the tibial growth plate (34) .…”

“…Further, MMP‐9 null mice exhibit abnormal skeletal growth plate vascularization and ossification (40) . Growth factors present in the long bone increase MMP‐2, MMP‐9, and MMP‐13 expression during chondrocyte maturation and growth plate remodeling 33, 36‐38) . Matrix vesicles contain gelatinases (MMP‐2 and MMP‐9), stromelysin, and collagenase‐3 (MMP‐13), suggesting a role for these MMPs in matrix mineralization of the growth plate (35, 41) .…”

Cartilage morphogenetic proteins: role in joint development, homoeostasis, and regeneration

“…37 Insulin-like growth factor, connective tissue growth factor, parathyroid hormone, and other related factors have an important role in chondrocytes. [38][39][40][41][42] The stability of the phenotype of articular chondrocytes is critically dependent on cell shape and cell density. The geometry of the cell culture is critical for chondrocyte gene expression.…”

Mechanism of Mineralization of Collagen‐Based Connective Tissues

“…In many tissues, OPN is cleaved by stromelysin-1 (MMP-3) and matrilysin (MMP-7) into smaller fragments [81]. Since MMP-3 is expressed in the growth plate, bone, and dentin [82,83] and matrilysin is also expressed in the growth plate [84] it is conceivable that the most active forms participating in the mineralization process are OPN fragments.…”