SummaryBackground and objectives The kidney is the organ most commonly involved in systemic amyloidosis. This study reports the largest clinicopathologic series of renal amyloidosis.

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Background: Coupling of bone degradation to subsequent bone formation requires recruitment of osteoblast precursors. Results: Osteoclasts produce sphingosine 1-phosphate (S1P), which stimulates mesenchymal (skeletal) stem cell migration by activating kinase signaling pathways. Conclusion: Coupling of bone resorption to bone formation involves S1P-mediated recruitment of osteoblastic cells. Significance: Enhancing kinase signaling in osteoblastic cells may be a novel approach to enhance bone formation.

In young adults, bone lost through osteoclast-mediated resorption is precisely replaced in both location and amount. Understanding how these two processes are coupled is crucial to advancing treatments for osteoporosis, a disease that progresses when the processes become uncoupled. We documented that osteoclasts secrete the mammalian integration 1 gene that is the homolog of Drosophila Wngless (Wnt) 10b, bone morphogenetic protein 6 (BMP6), and the chemokine sphingosin 1 phosphate (S1P) to promote mesenchymal cell mineralization in vitro. During bone resorption, TGF-β1 is released from the bone extracellular matrix and activated by osteoclasts. Thus, TGF-β1 levels are elevated during the resorption phase of bone turnover. We therefore investigated the influences of TGF-β1 on osteoclast-mediated support of mineralization. TGF-β1 increased osteoclast production of Wnt10b, but not BMP6 or S1P. Blocking Wnt10b activity with the Wnt signaling inhibitor Dickkoph-related protein 1 suppressed the ability of TGF-β-treated osteoclast-conditioned media to promote osteoblast mineralization. Examination of TGF-β signaling in osteoclasts revealed that induction of Wnt10b expression was dependent on Smad2/3 activation and independent from TGF-β1 stimulation of protein kinase B (AKT) or MAPK kinase. TGF-β1-treated osteoclast-conditioned media from cells with blocked Smad signaling exhibited a reduced ability to support mineralization, demonstrating the importance of Smad signaling in this response. Parallel cultures with suppressed TGF-β activation of AKT or MAPK kinase signaling retained their ability to elevate mineralization. These results demonstrate that TGF-β1 stimulates Wnt10b production in osteoclasts, which may enhance restoration of the bone lost during the resorptive phase of bone turnover.

The traditional model of hematopoiesis is based on unidirectional maturation of hematopoietic precursors into lineage-committed cells. However, recent studies indicate that mature B lymphocytes may demonstrate significant lineage plasticity. We and others have reported transdifferentiation of follicular lymphomas (FLs) into clonally related histiocytic/dendritic cell neoplasms. Here, we describe 2 patients with FL who developed clonally related Langerhans cell neoplasms. The first was a 52-year-old man diagnosed with FL, grade 1. He received immunochemotherapy and had stable disease for 8 years. He then developed increasing lymphadenopathy, and lymph node biopsy showed Langerhans cell sarcoma with no evidence of FL. The second patient was a 77-year-old woman who presented with lymphadenopathy, an abdominal mass, and pulmonary nodules. Lymph node biopsy showed both Langerhans cell histiocytosis and minimal involvement by FL, grade 1. In each case, a combination of immunoglobulin gene rearrangement and fluorescence in situ hybridization studies provided evidence to support a clonal relationship between the FL and Langerhans cell neoplasm. These cases provide striking examples of neoplastic transdifferentiation and expand the spectrum of lesions clonally identical to otherwise typical FL. Awareness of this phenomenon may aid in diagnosis when histologically dissimilar tumors arise synchronously or metachronously in patients with lymphoma.