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John D Termine, PhD, one of the first members and former councilor of the American Society for Bone and Mineral Research (ASBMR) (1984-1987), former vice president at Eli Lilly and Company, and esteemed investigator in bone and mineral metabolism, died in Kiawah Island, SC, on June 3, 2021, holding the hand of his wife of 60 years, Virginia. John is survived by his wife, Virginia; their children, Mary, John, Theresa, and Anne; 10 grandchildren; and three great-grandchildren. Remembering Dr John D Termine: September 25, 1938 - June 3, 2021. [Extracted from the article]

Mechanical stimulation is crucial to bone growth and triggers osteogenic differentiation through a process involving Rho and protein kinase A. We previously cloned a gene ( AKAP13, aka BRX) encoding a protein kinase A-anchoring protein in the N-terminus, a guanine nucleotide-exchange factor for RhoA in the mid-section, coupled to a carboxyl region that binds to estrogen and glucocorticoid nuclear receptors. Because of the critical role of Rho, estrogen, and glucocorticoids in bone remodeling, we examined the multifunctional role of Akap13. Akap13 was expressed in bone, and mice haploinsufficient for Akap13 ( Akap13+/-) displayed reduced bone mineral density, reduced bone volume/total volume, and trabecular number, and increased trabecular spacing; resembling the changes observed in osteoporotic bone. Consistent with the osteoporotic phenotype, Colony forming unit-fibroblast numbers were diminished in Akap13+/- mice, as were osteoblast numbers and extracellular matrix production when compared to control littermates. Transcripts of Runx2, an essential transcription factor for the osteogenic lineage, and alkaline phosphatase ( Alp), an indicator of osteogenic commitment, were both reduced in femora of Akap13+/- mice. Knockdown of Akap13 reduced levels of Runx2 and Alp transcripts in immortalized bone marrow stem cells. These findings suggest that Akap13 haploinsufficient mice have a deficiency in early osteogenesis with a corresponding reduction in osteoblast number, but no impairment of mature osteoblast activity. © 2015 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Articular cartilage repair remains a challenging problem. Based on a high-throughput screening and functional analysis, we found that fluocinolone acetonide (FA) in combination with transforming growth factor beta 3 (TGF-β3) strongly potentiated chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). In an in vivo cartilage defect model in knee joints of immunocompromised mice, transplantation of FA/TGF-β3-treated hBMSCs could completely repair the articular surface. Analysis of the intracellular pathways revealed that FA enhanced TGF-β3-induced phosphorylation of Smad2 and Smad3. Additionally, we performed a pathway array and found that FA activates the mTORC1/AKT pathway. Chemical inhibition of mTORC1 with rapamycin substantially suppressed FA effect, and inhibition of AKT completely repressed chondrogenesis of hBMSCs. Inhibition of glucocorticoid receptor with mifepristone also suppressed FA effect, suggesting that FA involves binding to the glucocorticoid receptor. Comparative analysis with other glucocorticoids (triamcinolone acetonide [TA] and dexamethasone [DEX]) revealed the unique ability of FA to repair articular cartilage surgical defects. Analysis of intracellular pathways showed that the mTORC1/AKT pathway and the glucocorticoid receptor was highly activated with FA and TA, but to a lesser extent with DEX. Collectively, these results show a unique ability of FA to enhance TGF-β3-associated chondrogenesis, and suggest that the FA/TGF-β3 combination may be used as major inducer of chondrogenesis in vitro. Additionally, FA/TGF-β3 could be potentially applied in a clinical setting to increase the efficiency of regenerative approaches based on chondrogenic differentiation of stem cells. © 2015 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The article discusses a study which found that Wnt-induced secreted protein 1 (WISP-1/CCN4) regulates osteogenesis by enhancing bone morphogenetic protein 2 (BMP-2) activity. The study analyzed the influence of WISP-1 on integrin expression to understand how WISP-1 enhanced BMP-2 signaling. Based on antibody-blocking experiments, the researchers found the complete neutralization of the BMP-2 binding to bone marrow stromal cells (BMSC) by treatment with anti-integrin α5β1 antibody.