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Shwachman-Diamond syndrome (SDS) is a rare and clinically heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Although SDS was described more than 50 years ago, its molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single-cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from patients with SDS. We generated a single-cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor beta (TGF-[beta]) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGF-[beta] inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGF-[beta]3 and other TGF-[beta] pathway members were elevated in SDS patient blood plasma. These data establish the TGF-[beta] pathway as a candidate biomarker and therapeutic target in SDS and translate insights from single-cell biology into a potential therapy., Introduction Shwachman-Diamond syndrome (SDS) is an inherited bone marrow (BM) failure syndrome associated with biallelic, hypomorphic mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS is a pleiotropic protein that facilitates [...]

Wnt signaling increases bone mass by stimulating osteoblast lineage commitment and expansion and forms the basis for novel anabolic therapeutic strategies being developed for osteoporosis. These strategies include derepression of Wnt signaling by targeting secreted Wnt pathway antagonists, such as sclerostin. However, such therapies are associated with safety concerns regarding an increased risk of osteosarcoma, the most common primary malignancy of bone. Here, we analyzed 5 human osteosarcoma cell lines in a high-throughput screen for epigenetically silenced tumor suppressor genes and identified Wnt inhibitory factor 1 (WIF1), which encodes an endogenous secreted Wnt pathway antagonist, as a candidate tumor suppressor gene. In vitro, WIF1 suppressed [beta]-catenin levels in human osteosarcoma cell lines, induced differentiation of human and mouse primary osteoblasts, and suppressed the growth of mouse and human osteosarcoma cell lines. Wif1 was highly expressed in the developing and mature mouse skeleton, and, although it was dispensable for normal development, targeted deletion of mouse Wif1 accelerated development of radiation-induced osteosarcomas in vivo. In primary human osteosarcomas, silencing of WIF1 by promoter hypermethylation was associated with loss of differentiation, increased [beta]-catenin levels, and increased proliferation. These data lead us to suggest that derepression of Wnt signaling by targeting secreted Wnt antagonists in osteoblasts may increase susceptibility to osteosarcoma., Introduction Osteosarcoma is the most common primary malignancy of bone, and the third most common cancer in adolescents (1). Risk factors for osteosarcoma include states associated with increased osteoblast proliferation, [...]

Osteoporosis results from an imbalance in skeletal remodeling that favors bone resorption over bone formation. Bone matrix is degraded by osteoclasts, which differentiate from myeloid precursors in response to the cytokine RANKL. To gain insight into the transcriptional regulation of bone resorption during growth and disease, we generated a conditional knockout of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). Deletion of Nfatc1 in young mice resulted in osteopetrosis and inhibition of osteoclastogenesis in vivo and in vitro. Transcriptional profiling revealed NFATc1 as a master regulator of the osteoclast transcriptome, promoting the expression of numerous genes needed for bone resorption. In addition, NFATc1 directly repressed osteoclast progenitor expression of osteoprotegerin, a decoy receptor for RANKL previously thought to be an osteoblast-derived inhibitor of bone resorption. "Cherubism mice", which carry a gain-of-function mutation in SH3-domain binding protein 2 (Sh3bp2), develop osteoporosis and widespread inflammation dependent on the proinflammatory cytokine, TNF-[alpha]. Interestingly, deletion of Nfatc1 protected cherubism mice from systemic bone loss but did not inhibit inflammation. Taken together, our study demonstrates that NFATc1 is required for remodeling of the growing and adult skeleton and suggests that NFATc1 may be an effective therapeutic target for osteoporosis associated with inflammatory states., Introduction Osteoporosis, the most common pathologic condition resulting from excessive bone destruction, afflicts 10 million Americans over the age of 50 and results in 1.5 million fractures annually (1), (2). [...]

The most common disease caused by excessive osteoclast-mediated bone destruction is osteoporosis. In addition, systemic and local bone loss complicates some inflammatory conditions. More insight into the molecular control of [...]