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The morbidity and mortality associated with impaired͞delayed fracture healing remain high. Our objective was to identify a small nonpeptidyl molecule with the ability to promote fracture healing and prevent malunions. Prostaglandin E2 (PGE2) causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton. However, due to side effects, PGE2 is an unacceptable therapeutic option for fracture healing. PGE2 mediates its tissue-specific pharmacological activity via four different G protein-coupled receptor subtypes, EP1, -2, -3, and -4. The anabolic action of PGE2 in bone has been linked to an elevated level of cAMP, thereby implicating the EP2 and͞or EP4 receptor subtypes in bone formation. We identified an EP2 selective agonist, CP-533,536, which has the ability to heal canine long bone segmental and fracture model defects without the objectionable side effects of PGE2, suggesting that the EP2 receptor subtype is a major contributor to PGE2's local bone anabolic activity. The potent bone anabolic activity of CP-533,536 offers a therapeutic alternative for the treatment of fractures and bone defects in patients.T he skeleton has the unique ability to repair and heal itself after injury (1, 2). This process is a cascade of synchronized events involving many systemic and local signaling molecules (3). However, in Ϸ10% of cases, fractured bones heal more slowly (malunion) or fail to heal (nonunion), requiring additional costly medical intervention to repair the fracture (4). These malunions and nonunions cause significant patient morbidity, significantly limiting quality of life and increasing healthcare costs. New therapies that could ensure rapid healing of fractures and bone defects would lessen the need for further medical intervention and greatly reduce the morbidity and loss of independence associated with immobilization.The discovery of bone morphogenetic proteins has increased our understanding of the cascade of events that takes place during fracture healing. Several clinical studies demonstrate the capability of these proteins to induce and facilitate this process (5-8). However, the cost effectiveness, degree of clinical benefit, and long-term safety of these therapies have not been fully elucidated. These issues prompted us to identify additional mechanisms and pathways involved in bone formation that could be modulated with a nonpeptidyl small molecule. Such a compound could be used as a therapy to promote fracture healing and prevent malunions. Prostaglandin E 2 (PGE 2 ) has been shown to have multiple biological effects in many tissues, including bone. PGE 2 causes significant increases in bone mass and bone strength when administered systemically or locally to the skeleton (9-11). However, due to side effects, including diarrhea, lethargy, and flushing, PGE 2 is an unacceptable therapeutic option for bone healing. PGE 2 binds to and elicits its pharmacological activity from four different cell surface receptor subtypes, EP1, -2, -3, and -4 (12-16). T...

Understanding periodontal ligament (PDL) biology and developing an effective treatment for bone and PDL damage due to periodontitis have been longstanding aims in dental medicine. Here, we first demonstrated by cell lineage tracing and mineral doublelabeling approaches that murine PDL progenitor cells display a 2-and 3-fold higher mineral deposition rate than the periosteum and endosteum at the age of 4 weeks, respectively. We next proved that the pathologic changes in osteocytes (Ocys; changes from a spindle shape to round shape with a >50% reduction in the dendrite number/length, and an increase in SOST) are the key pathologic factors responsible for bone and PDL damage in periostin-null mice (a periodontitis animal model) using a newly developed 3-dimensional FITCImaris technique. Importantly, we proved that deleting the Sost gene (a potent inhibitor of WNT signaling) or blocking sclerostin function by using the mAb in this periodontitis model significantly restores bone and PDL defects (n = 4-5; P < 0.05). Together, identification of the key contribution of the PDL in normal alveolar bone formation, the pathologic changes of the Ocys in periodontitis bone loss, and the novel link between sclerostin and Wnt signaling in the PDL will aid future drug development in the treatment of patients with

Macrophages seed all tissues in which they have the ability, in specific and rare instances, to fuse with themselves and to differentiate into osteoclasts in bone or into giant cells in chronic inflammatory reactions. Although these cells play a central role in osteoporosis and in foreign body rejection, respectively, the molecular mechanism used by macrophages to fuse remains poorly understood. Macrophages might also fuse with somatic and tumor cells to promote tissue repair and metastasis, respectively. We reported that CD44 expression is highly induced in macrophages at the onset of fusion in which it plays a role. We report now that the intracellular domain of CD44 (CD44ICD) is cleaved in macrophages undergoing fusion and that presenilin inhibitors prevent the release of CD44ICD and fusion. We also show that CD44ICD promotes the fusion of tissue macrophages and bone marrow-derived macrophages. IntroductionMacrophages seed all tissues and have the capacity, in specific and rare instances, to undergo homotypic fusion and to differentiate into multinucleate osteoclasts or giant cells, in bone or in chronic inflammatory reactions, respectively. Multinucleation endows macrophages with the ability to resorb components located extracellularly such as bone and foreign bodies, respectively. 1,2 In as much as osteoclasts are essential for the remodeling of bone, they are chiefly responsible for the loss of bone that leads to osteoporosis. Osteoclasts are also responsible for the local loss of bone that results from inflammation, such as in rheumatoid arthritis and in periodontal disease. Giant cells differentiate around foreign bodies such as pathogens, implants, and transplants that they resorb.Increasing evidence suggests that macrophages possess the ability to fuse also with somatic cells to repair tissues and organs and with tumor cells to trigger the metastatic process. 2 So macrophages, which are ubiquitously present in tissues where they perform a wide array of functions, might be endowed with a larger repertoire of biologic activities than originally anticipated. 3 The molecular mechanisms used by macrophages to adhere to, and to fuse with each other, and possibly with other cells, is an essential step that remains to be characterized. Indeed, cell-to-cell fusion itself, whether it concerns that of sperm cells with oocytes or myoblasts with myoblasts, leading to fertilization and muscle development, respectively, remains unclear. 4 To gain insight into the fusion mechanism of macrophages, we had subjected fusing rat alveolar macrophages to genome-wide oligonucleotide microarray, an approach that revealed the transiently induced expression of presenilin 2 (PS2), a protein associated with Alzheimer disease (for a review, see Hutton and Hardy 5 ). The fact that the deletion of the ps1 gene in mice leads to severe skeletal defects, 6 and that the deletion of the ps2 gene enhances the embryonic lethal phenotype of ps1 deletion, 7 triggered our interest in PS.Presenilins (PS1 and PS2) are transmembrane proteins ide...