Substantial data support major roles for bone-derived TGF-␤ 1 and tumor-derived parathyroid hormone-related protein (PTHrP) in the vicious cycle of local bone destruction that characterizes osteolytic metastases. Tumor-produced PTHrP stimulates osteoclastic bone resorption to result in the bone destruction associated with breast cancer metastases (1, 2). Neutralizing antibodies to PTHrP not only decreased osteoclastic bone resorption but also inhibited the development of metastases to bone by the human breast cancer cell line, MDA-MB-231 (3). TGF-␤, stored in bone matrix (4) and released locally in active form during osteoclastic resorption (5), stimulates PTHrP production by tumor cells (6 -8). A dominantnegative TGF-␤ type II receptor (T␤RII⌬cyt) stably expressed in the MDA-MB-231 breast cancer line rendered the cells unresponsive to TGF-␤ and inhibited TGF-␤-induced PTHrP secretion and the development of bone metastases in a mouse model. This dominant-negative type II blockade was reversed by a constitutively active TGF-␤ type I receptor (T␤RI(T204D)). Furthermore, transfection of the cDNA for PTHrP into the dominant-negative MDA-MB-231 line also increased PTHrP production and accelerated bone metastases (9). These published data establish that TGF-␤ in bone can promote osteolysis by increasing PTHrP secretion from breast cancer cells. They do not, however, exclude contributions from other TGF-␤-responsive tumor factors. Here we demonstrate that PTHrP is the central mediator of TGF-␤-induced osteolytic metastasis. We also show that TGF-␤ increases PTHrP secretion from MDA-MB-231 cells by signaling through both Smad and p38 MAP kinase pathways.

A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrActUsing the Bmp2 floxed/3.6Col1a1-Cre (Bmp2-cKO od ) mouse model, we have observed severe defects in odontogenesis and dentin formation with the removal of the Bmp2 gene in early-polarizing odontoblasts. The odontoblasts in the Bmp2-cKO od do not mature properly and fail to form proper dentin with normal dentinal tubules and activate terminal differentiation, as reflected by decreased Osterix, Col1a1, and Dspp expression. There is less dentin, and the dentin is hypomineralized and patchy. We also describe an indirect effect of the Bmp2 gene in odontoblasts on formation of the vascular bed and associated pericytes in the pulp. This vascular niche and numbers of CD146+ pericytes are likely controlled by odontogenic and Bmp2-dependent VegfA production in odontoblasts. The complex roles of Bmp2, postulated to be both direct and indirect, lead to permanent defects in the teeth throughout life, and result in teeth with low quantities of dentin and dentin of poor quality.

BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, resulting in the coronavirus disease COVID-19) is highly transmissible among people. Asymptomatic infections are also an important source of infection. Here, we aimed to further clarify the epidemiologic and clinical characteristics of asymptomatic SARS-CoV-2 infections. METHODS We identified close contacts of confirmed COVID-19 cases in northeast Chongqing who were RT-PCR+ yet remained asymptomatic throughout their infections. We stratified this cohort by normal versus abnormal findings on chest CT, and compared the strata regarding comorbidities, demographics, laboratory findings, viral transmission and other factors. RESULTS Between January and March, 2020, we identified and hospitalized 279 RT-PCR+ contacts of COVID-19 patients. Of these, 63 (23%) remained asymptomatic until discharge; 29 had abnormal and 34 had normal chest CT findings. The mean cohort age was 39.3 years, and 87.3% had no comorbidities. Mean time to diagnosis after close contact with a COVID-19 index patient was 16.0 days (range 1 to 29), and 13.4 days and 18.7 days for those with abnormal and normal CT findings, respectively (p < 0.05). Nine subjects (14.3%) transmitted the virus to others; 4 and 5 were in the abnormal and normal CT strata, respectively. The median length of nucleic acid turning negative in asymptomatic COVID-19 patients was 13 days, compared to 10.4 days in those with normal chest CT (p < 0.05). CONCLUSIONS A portion of these asymptomatic individuals, with and without abnormal chest CT scans, were capable of transmitting the virus to others. Given the frequency and potential infectiousness of asymptomatic infections, testing of traced contacts is essential. Studies of the impact of treatment on asymptomatic RT-PCR+ individuals on disease progression and transmission should be undertaken.

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SummaryWe generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO ob ) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO ob mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO ob osteoblasts. Deletion of Bmp2 in osteoblasts also leads to defective mesenchymal stem cells (MSCs), which correlates with the reduced microvascular bed in the periosteum and trabecular bones. Expression of several MSC marker genes (a-SMA, CD146 and Angiopoietin-1) in vivo, in vitro CFU assays and deletion of Bmp2 in vitro in a-SMA + MSCs support our conclusions. Critical roles of Bmp2 in osteoblasts and MSCs are a vital link between bone formation, vascularization and mesenchymal stem cells.