PPARgamma2 expression in growth plate chondrocytes is regulated by p38 and GSK-3.

Although peroxisome proliferator activated receptor (PPAR)gamma remains a critical regulator of preadipocyte differentiation, new roles have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity and atherosclerosis. Despite the demonstration of PPARgamma expression in chondrocytes, its role and the pathways affecting its expression and activity in chondrocytes remain largely unknown. We investigated the effects of PPARgamma activation on chondrocyte differentiation and its participation in chondrocyte lipid metabolism.

Human stanniocalcin-1 or -2 expressed in mice reduces bone size and severely inhibits cranial intramembranous bone growth.

Stanniocalcin-1 (STC1) and -2 (STC2) are highly related, secreted, homodimeric glycoproteins that are significantly upregulated by different forms of stress including high phosphate levels. Transgenic mice that constitutively express either human STC1 or STC2 exhibit intra-uterine growth restriction and permanent post-natal growth retardation. STC1 is expressed in chondrocytic and osteoblastic cells during murine development and can enhance differentiation of calvarial cells in culture.

Genome-wide analyses of gene expression during mouse endochondral ossification.

Background: Endochondral ossification is a complex process involving a series of events that are initiated by the establishment of a chondrogenic template and culminate in its replacement through the coordinated activity of osteoblasts, osteoclasts and endothelial cells. Comprehensive analyses of in vivo gene expression profiles during these processes are essential to obtain a complete understanding of the regulatory mechanisms involved.

Methodology/principal Findings: To address these issues, we completed a microarray screen of three zones derived from manually segmented embryonic mouse tibiae.

C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways.

Background: C-type natriuretic peptide (CNP) has recently been identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanisms mediating its effects are not completely understood.

Results: We demonstrate in a tibia organ culture system that pharmacological inhibition of p38 blocks the anabolic effects of CNP. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization.

Inhibition of p38 MAPK signaling in chondrocyte cultures results in enhanced osteogenic differentiation of perichondral cells.

Chondrocytes and osteoblasts originate from the same progenitor cell; however, both are characterized by distinct gene expression profiles once they are differentiated. Signals from differentiating chondrocytes, such as Indian hedgehog (Ihh), regulate the differentiation of osteoblast precursor cells. The MAPK pathways play important roles in controlling the differentiation of both chondrocytes and osteoblasts, with the p38 pathway being particularly relevant in skeletal cells.

CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts.

CCN2 is induced by transforming growth factor-beta (TGFbeta) in fibroblasts and is overexpressed in connective tissue disease. CCN2 has been proposed to be a downstream mediator of TGFbeta action in fibroblasts; however, the role of CCN2 in regulating this process unclear. By using embryonic fibroblasts isolated from ccn2-/- mice, we showed that CCN2 is required for a subset of responses to TGFbeta.

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation.

Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies.

Immunophenotyping of macrophages in human pulmonary tuberculosis and sarcoidosis.

Classic studies of tuberculosis (TB) revealed morphologic evidence of considerable heterogeneity of macrophages (MØs), but the functional significance of this heterogeneity remains unknown. We have used newly available specific antibodies for selected membrane and secretory molecules to examine the phenotype of MØs in situ in a range of South African patients with TB, compared with sarcoidosis. Patients were human immunodeficiency virus-negative adults and children, and the examined biopsy specimens included lung and lymph nodes.

RhoA/ROCK signaling suppresses hypertrophic chondrocyte differentiation.

Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation.

MAP kinases in chondrocyte differentiation.

The majority of the vertebrate skeleton develops through the process of endochondral ossification and involves successive steps of chondrogenesis, chondrocyte proliferation, and hypertrophic chondrocyte differentiation. Interruption of this program through gene mutations and hormonal or environmental factors contributes to numerous diseases, including growth disorders and chondrodysplasias. While a large number of growth factors and hormones have been implicated in the regulation of chondrocyte biology, relatively little is known about the intracellular signaling pathways involved.

p38 MAP kinase signalling is required for hypertrophic chondrocyte differentiation.

Longitudinal growth of endochondral bones is accomplished through the co-ordinated proliferation and hypertrophic differentiation of growth plate chondrocytes. The molecular mechanisms and signalling cascades controlling these processes are not well understood. To analyse the expression and roles of p38 mitogen-activated protein kinases in this process, we have established a micromass system for the reproducible hypertrophic differentiation of mouse mesenchymal limb bud cells.