Osteoblasts are specialized fibroblasts that secrete and calcifya specific matrix. Their lineage specification from mesenchymalstems cells is regulated by a plethora of signals. A range ofcytokines modulate osteoblast differentiation, including bonematrix–derived TGF-ß, bone morphogenic protein2 (BMP-2), BMP-4, and BMP-7, and their inhibitors noggin, chordin,gremlin, and sclerostin, the last identified by positional cloningof families with increased bone mass. Similarly, numerous hormonesimpact osteoblast function positively including IGF-1, parathyroidhormone (PTH), PTH-related protein (PTHrP), 1,25(OH)2D3, leptin,glucocorticoids, the Notch pathway, and members of the leukemiainhibitory factor/IL-6 family.
Transcription factors that regulate the osteoblast include arange of homeodomain proteins: the activator protein (AP) familymembers Jun, Fos, and Fra, Smads, CCAAT/enhancer binding proteinß (C/EBPß) and C/EBP, lymphoid-enhancingfactor (a Wnt effector), activating transcription factor 4,Runt-related transcription factor 2 (Runx2), and osterix, thelast 3 of which are considered master genes for osteoblast differentiation.In contrast to the osteoclast (see below), the osteoblast’sbest-characterized intracellular signaling pathway is the p42/44MAPK system.
Osteoblasts ligate existing matrix via ß1 integrins,forming a monolayer that is linked by cadherins. Once active,the cells secrete a matrix containing type I collagen and smallerbut significant amounts of osteocalcin, matrix gla protein,osteopontin, bone sialoprotein, many minor components, and,importantly, growth factors such as BMPs and TGF-ß.Key ectoproteins, including progressive ankylosis gene (ANK)and tissue nonspecific alkaline phosphatase (TNAP), export pyrophosphategenerated intracellularly and cleave this small-molecule inhibitorof calcification, respectively (34). In contrast to their proapoptoticrole in osteoclasts, bisphosphonates increase osteoblast lifespanand perhaps function (35).
The text below focuses on Wnt signaling in osteoblasts and therole of these cells as supporters of the HSC niche and targetsfor osteoclastogenic hormones. Detailed reviews of osteoblastbiology are available (36-40).