P. Mark Bartold

Growth factor modulation of mitogenic responses and proteoglycan synthesis by human periodontal fibroblasts

In order to understand the relationship between specific growth factors and matrix synthesis by periodontal cells, we have investigated the effects of platelet‐derived growth factor BB (PDGF‐BB), insulin‐like growth factor‐I (IGF‐1), and growth hormone on DNA and proteoglycan synthesis by cultured human gingival and periodontal ligament fibroblasts in vitro. PDGF‐BB and IGF‐1, but not growth hormone, were mitogenic for both periodontal ligament fibroblasts and gingival fibroblasts, although the periodontal ligament cells responded more strongly. The mitogenic response was accompanied by alterations in expression of matrix proteoglycan mRNA. For both the gingival and periodontal ligament cells, there was a decrease in mRNA for decorin and an increase in mRNA for versican following exposure to IGF‐1 and PDGF‐BB. Although no change was seen in response to PDGF, biglycan mRNA level was increased by IGF‐1 in periodontal ligament fibroblasts. With the gingival fibroblats, biglycan mRNA levels were unaffected by IGF‐1, PDGF‐BB, or growth hormone. These findings suggest variable responses of fibroblasts to growth factors depending upon anatomical site within the periodontium. Moreover, there appears to be a correlation between cell proliferation and the types of proteoglycan synthesised with decorin expression being suppressed, and versican being increased during fibroblast proliferation. J. Cell. Physiol. 174:353–361, 1998.

Growth hormone induces bone morphogenetic proteins and bone-related proteins in the developing rat periodontium.

The hypothesis that growth hormone (GH) up‐regulates the expression of enzymes, matrix proteins, and differentiation markers involved in mineralization of tooth and bone matrices was tested by the treatment of Lewis dwarf rats with GH over 5 days. The molar teeth and associated alveolar bone were processed for immunohistochemical demonstration of bone morphogenetic proteins 2 and 4 (BMP‐2 and ‐4), bone morphogenetic protein type IA receptor (BMPR‐IA), bone alkaline phosphatase (ALP), osteocalcin (OC), osteopontin (OPN), bone sialoprotein (BSP), and E11 protein (E11). The cementoblasts, osteoblasts, and periodontal ligament (PDL) cells responded to GH by expressing BMP‐2 and ‐4, BMPR‐IA, ALP, OC, and OPN and increasing the numbers of these cells. No changes were found in patterns of expression of the late differentiation markers BSP and E11 in response to GH. Thus, GH evokes expression of bone markers of early differentiation in cementoblasts, PDL cells, and osteoblasts of the periodontium. We propose that the induction of BMP‐2 and ‐4 and their receptor by GH compliments the role of GH‐induced insulin‐like growth factor 1 (IGF‐1) in promoting bone and tooth root formation.

Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis

OBJECTIVEnHistone deacetylase 1 (HDAC1) is highly expressed in the synovium of RA patients. Thus we aimed to investigate a novel HDAC inhibitor (HDACi), NW-21, designed to target HDAC1. The effect of NW-21 on osteoclast formation and activity, cytokine and chemokine expression in vitro and arthritis in mice was assessed.nnnMETHODSnThe effects on human osteoclast formation and activity derived from human blood monocytes stimulated with receptor activator of nuclear factor κB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of NW-21 was assessed using human monocytes stimulated with either TNF-α or lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 (MCP-1), TNF-α, macrophage inflammatory protein 1α (MIP-1α), IL-1 and RANTES (regulated on activation, normal T cell expressed and secreted) was assessed. The effect of NW-21 in the collagen antibody-induced arthritis model was assessed following daily oral administration at 5 mg/kg/day. The HDAC1 inhibitors NW-21 and MS-275 were compared with a broad-acting HDACi, 1179.4b. Effects on inflammation and bone were assessed using paw inflammation scoring, histology and live animal micro-CT.nnnRESULTSnNW-21 suppressed osteoclast formation and activity as well as significantly reducing mRNA expression of MCP-1 and MIP-1α in monocytes stimulated by lipopolysaccharide or TNF-α (P < 0.05) in vitro. Only inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone loss in the arthritis model.nnnCONCLUSIONnThe results indicate that inhibitors targeting HDAC1, such as NW-21 and MS-275, may be useful for treating RA, as such drugs can simultaneously target both inflammation and bone resorption.

From Histoalchemy to Molecular Marvels: A Sojourn through Periodontal Connective Tissue Research

INTRODUCTION This essay is written to highlight how what often may be perceived to be unfashionable research may often lead to exciting new developments which ultimately can have an impact over a broad range of areas. While this piece focuses mainly on proteoglycans, it must be recognized that many connective tissue stalwarts over the past 25 years have contributed enormously to our understanding of the molecular composition of the periodontal connective tissues and how these regulate cell and tissue function. The story of how we have come to view proteoglycans parallels similar research on the myriad other extracellular matrix components of the periodontal connective tissues. In 1977, as a dental student, I made an appointment to see my Dean (Professor John Thonard) to discuss the possibility of doing a summer research project in one of the Dental School laboratories at the University of Adelaide. Not one to lose an opportunity, John Thonard immediately made arrangements for me to work in his laboratory and commence a study on proteoglycans in human gingivae. Little did I know this simple appointment was to change my career irreversibly. In 1977, very little was known of proteoglycans. They certainly did not have any fancy names, and we had only a limited idea about what they did (Comper and Laurent, 1978). The research on these rather obscure molecules had been restricted almost solely to cartilage. Why on earth did John Thonard think they would be in gums? Unknown to me at the time, another character soon to make another impact on my life was Dr. Ole Wiebkin. Dr. Wiebkin-a supreme enthusiast, optimist, and teacher-had returned to John Thonards laboratory after a stint at the Kennedy Institute in London. The stage was set-a lab with a focused interest and a naYve student!