Localization of Matrix Metalloproteinases, (MMPs) Their Tissue Inhibitors, and Vascular Endothelial Growth Factor (VEGF) in Growth Plates of Children and Adolescents Indicates a Role for MMPs in Human Postnatal Growth and Skeletal Maturation

Abstract

Numerous studies have focused on the expression, regulation, and biological significance of matrix metalloproteinases (MMPs) in the growth plate. Findings in mouse knockout models and in vitro data from various species indicate that MMPs not only degrade extracellular matrix components but may regulate the activity of local growth factors. In this study we investigated the presence, distribution, and activity of various MMPs and inhibitors, tissue transglutaminase (tTG or TG2) and vascular endothelial growth factor (VEGF) in the human child and adolescent growth plates by means of immunohistochemistry and gelatin zymography. Tissue was derived during orthopedic surgery (epiphysiodesis) in two prepubertal and four pubertal patients.MMP-2 and MMP-14 were present in reserve cell chondrocytes. MMP-14 was the most prominent MMP within all zones of the growth plate including proliferating chondrocytes. MMP-1 and MMP-13 (collagenases 1 and 3), MMP-9 (gelatinases B), MMP-10, and MMP-11 (stromelysins) and VEGF were positive in hypertrophic chondrocytes and osteoblasts. MMP-2 showed the same expression pattern but was negative in osteoblasts. Osteoclasts stained positive for MMP-9, MMP-2, and TG2. Tissue inhibitor of MMP (TIMP)-1 was present in all zones of the growth plate, osteoblasts, and osteoclasts; TIMP-2 was found in hypertrophic chondrocytes and osteoblasts. In summary, the presence of MMPs, TIMPs, TG2, and VEGF in our study indicated that the MMPs are relevant in growth plate physiology during the postnatal period in humans. The specific location of MMP expression within the growth plate may be the basis for further studies on the role of MMPs in the local regulation of chondrocyte differentiation, proliferation, and ossification at the chondroosseus junction.

Association of bone age with overweight and obesity in children in the age group of 8 to 11 years

“…This complex cascade of events includes parathyroid hormone related peptide (PTHrP), Indian hedgehog, matrix metallo proteinases and vascular endothelial growth factor (VEGF), which are involved in coordinating cellular growth, cellular differentiation, apoptosis, extracellular matrix remodelling and angiogenesis. 8 Estrogens, androgens and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis influence the activity of these factors and the progression of skeletal maturation. 9 One of the adverse effects of obesity in children is advancement of bone age.…”

Genetic expression of MMP-Matrix-mettalo-proteinases (MMP-1 and MMP-13) as a function of anterior mandibular repositioning appliance on the growth of mandibular condylar cartilage with and without administration of Insulin like growth factor (IGF-1) and Transforming growth factor-B (TGF-β)

“…MMPs also appear to be involved in apoptosis of growth plate chondrocytes, as well as in the modulation of biologic activity of relevant growth factors, their receptors, cytokines, adhesion receptors, and a variety of enzymes. 18 Subsequently, mandibular condyle is generated by the endochondral ossification like that of long bone; however, its pattern of development is different from that of the long bone. MCC, often classified as a secondary cartilage, develops from already differentiated cells into periosteum-like cells, rather than from the undifferentiated mesenchymal cells.…”

Matrix metalloproteinases in bone development and pathology: current knowledge and potential clinical utility

“…40 Due to its preferential digestion of type II collagen over other collagen types, MMP-13, which is derived from chondrocytes, synovial cells, and osteoblasts, is considered to be the most important collagenase for the degradation of cartilage. 3,41 The proenzyme form of MMP-13 is ~60 kDa in size and can be activated by MMP-2, MMP-3, MMP-14, and plasmin. 42 The expression and type II collagen degradation activity of the 48 kDa active MMP-13 can also be upregulated by ECM proteins such as type X collagen 43 and periostin.…”

“…MMP-16 present in osteoblasts and osteocytes 41 acts by breaking down ECM proteins such as high-density fibrillar type I collagen, thus promoting bone growth and development. 73 The mechanism of ECM degradation via MMP-16 is necessary for the proper functioning of mesenchymal cells expressed on skeletal tissue.…”

“…41,76 Mice overexpressing TIMP-1 in osteoblasts were found by Geoffroy et al 77 to have increased trabecular bone volume and decreased bone turnover, hence indicative of an important regulatory role in bone formation and remodeling that is likely to be dependent on its MMP inhibitory activity. TIMP-2 has also been found to be expressed by hypertrophic chondrocytes and osteoblasts, 41 and both TIMP-1 and TIMP-2 are able to directly stimulate the bone-resorbing activity of osteoclasts in vitro at physiological concentrations, and this is likely to be independent of their inhibition of MMPs. 78 Other TIMP members including TIMP-3 and TIMP-4 are also expressed in bone and joint tissues, and an increased expression of these have been associated with OA.…”