Regulation of Growth Plate Chondrogenesis by Bone Morphogenetic Protein-2¹

Abstract

Bone morphogenetic proteins (BMPs) regulate embryonic skeletal development. We hypothesized that BMP-2, which is expressed in the growth plate, also regulates growth plate chondrogenesis and longitudinal bone growth. To test this hypothesis, fetal rat metatarsal bones were cultured for 3 days in the presence of recombinant human BMP-2. The addition of BMP-2 caused a concentration-dependent acceleration of metatarsal longitudinal growth. As the rate of longitudinal bone growth depends primarily on the rate of growth plate chondrogenesis, we studied each of its three major components. BMP-2 stimulated chondrocyte proliferation in the epiphyseal zone of the growth plate, as assessed by [(3)H]thymidine incorporation. BMP-2 also caused an increase in chondrocyte hypertrophy, as assessed by quantitative histology and enzyme histochemistry. A stimulatory effect on cartilage matrix synthesis, assessed by (35)SO(4) incorporation into glycosaminoglycans, was produced only by the highest concentration of BMP-2. These BMP-2-mediated stimulatory effects were reversed by recombinant human Noggin, a glycoprotein that blocks BMP-2 action. In the absence of exogenous BMP-2, Noggin inhibited metatarsal longitudinal growth, chondrocyte proliferation, and chondrocyte hypertrophy, which suggests that endogenous BMPs stimulate longitudinal bone growth and chondrogenesis. We conclude that BMP-2 accelerates longitudinal bone growth by stimulating growth plate chondrocyte proliferation and chondrocyte hypertrophy.

Nuclear Factor-κB (NF-κB) p65 Interacts with Stat5b in Growth Plate Chondrocytes and Mediates the Effects of Growth Hormone on Chondrogenesis and on the Expression of Insulin-like Growth Factor-1 and Bone Morphogenetic Protein-2

“…We have previously demonstrated that BMP-2 stimulates longitudinal bone growth and growth plate chondrogenesis (43), and BMP-2 expression and activity in growth plate chondrocyte function are regulated by NF-B p65 (7). In this study, we show that the NF-B p65 activation by GH also induces BMP-2 expression, which suggests that GH may promote growth plate chondrocyte function by activating both IGF-1 and BMP-2 activity.…”

Bone Morphogenetic Protein 2 Mediates Dentin Sialophosphoprotein Expression and Odontoblast Differentiation via NF-Y Signaling

“…Among the BMP family members, BMP2 has been extensively studied for its various biological functions, particularly during chondrogenic and osteogenic differentiations (27,28). BMP2 is expressed in mesenchymal cells (29,30) and promotes pluripotent mesenchymal cell commitment to the osteoblast lineage by regulating transcription factors such as Runx2/Smad cascade (31)(32)(33)(34)(35) and others (36,37).…”

BMP signaling stimulates cellular differentiation at multiple steps during cartilage development

“…Studies using cell culture systems have shown that BMPs generally stimulate hypertrophic differentiation of chondrocytes (7)(8)(9)(10)(11)(12). Studies analyzing the addition of different BMPs to bone explants have yielded variable results, including stimulation of hypertrophy (13), delay in hypertrophy (14), or delay in conversion of early hypertrophic chondrocytes to late hypertrophic chondrocytes (15). Retroviral expression of BMPs, constitutively active or dominant negative BMP receptors, or a BMP inhibitor in developing chicken limbs has shown that increased or decreased BMP action causes abnormal cartilage formation (16)(17)(18)(19).…”