The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone

Abstract

Histone deacetylase 4 (Hdac4) is known to control chondrocyte hypertrophy and bone formation. We have previously shown that parathyroid hormone (PTH) regulates many aspects of Hdac4 function in osteoblastic cells in vitro; however, in vivo confirmation was previously precluded by preweaning lethality of the Hdac4-deficient mice. To analyze the function of Hdac4 in bone in mature animals, we generated mice with osteoblast lineage-specific knockout of Hdac4 (Hdac4 ) by crossing transgenic mice expressing Cre recombinase under the control of a 2.3-kb fragment of the Col1a1 promoter with mice bearing loxP-Hdac4. The Hdac4 mice survive to adulthood and developed a mild skeletal phenotype. At age 12 weeks, they had short, irregularly shaped and stiff tails due to smaller tail vertebrae, with almost no growth plates. The tibial growth plate zone was also thinned, and Mmp13 and Sost mRNAs were increased in the distal femurs of Hdac4 mice. Immunohistochemistry showed that sclerostin was elevated in Hdac4 mice, suggesting that Hdac4 inhibits its gene and protein expression. To determine the effect of PTH in these mice, hPTH (1-34) or saline were delivered for 14 days with subcutaneously implanted devices in 8-week-old female Hdac4 and wild-type (Hdac4 ) mice. Serum CTX, a marker of bone resorption, was increased in Hdac4 mice with or without PTH treatment. Tibial cortical bone volume/total volume (BV/TV), cortical thickness (Ct.Th), and relative cortical area (RCA) were decreased in Hdac4 mice, but PTH caused no further decrease in Hdac4 mice. Tibial trabecular BV/TV and thickness were not changed significantly in Hdac4 mice but decreased with PTH treatment. These results indicate that Hdac4 inhibits bone resorption and has anabolic effects via inhibiting Mmp13 and Sost/sclerostin expression. Hdac4 influences cortical bone mass and thickness and knockout of Hdac4 prevents the catabolic effect of PTH in cortical bone. © 2018 American Society for Bone and Mineral Research.

Abaloparatide at the Same Dose Has the Same Effects on Bone as PTH (1-34) in Mice

“…(19) One of the major anabolic effects of PTH in vivo and in vitro is inhibition of sclerostin (Sost) expression, a glycoprotein secreted by late osteoblasts and osteocytes. (19,48,49) The main function of sclerostin is to inhibit bone formation through inhibition of the canonical Wnt/β-catenin pathway. (50,51) There appeared to be a difference in the effect of PTH (1-34) and abaloparatide on Sost expression.…”

Histone Acetylation as a Regenerative Target in the Dentine-Pulp Complex

“…Several studies have investigated the importance of HDACs in pulpal mineralisation processes and odontoblast differentiation in vitro (Duncan et al, 2012;Duncan et al, 2013;Paino et al, 2014), but further work is required to understand HDACs role during tooth development in vivo. Deletion of HDAC-4 in mice inhibited bone resorption and reduced thickness and cortical bone mass (Nakatani et al, 2016), and had the additional effect of inhibiting MMP-13 and Sost/ sclerostin expression (Nakatani et al, 2018). Dentally, a mouse model of HDAC-4 KO demonstrated altered mineralisation in the roots of developing teeth (Ono et al, 2016) and the volume of enamel and dentine ( Figure 1A).…”

“…Class I HDACs demonstrate ubiquitous expression, while class II show tissuespecific expression and cellular localisations (Montgomery et al, 2007). The importance of class II HDAC expression in mineralising tissues has been demonstrated in bone (Ricarte et al, 2016) and teeth (Klinz et al, 2012), with the individual isoforms, -6 (Westendorf et al, 2002), -5, and -4 (Nakatani et al, 2018), highlighted as being important cellular mediators which regulate osteoblast differentiation. HDACs' roles in the regulation of mineralisation and developmental cellular processes (Gordon et al, 2015), also make them attractive therapeutic targets for pharmacological inhibition (Richon et al, 1996).…”

Hepatic Osteodystrophy—Molecular Mechanisms Proposed to Favor Its Development

“…Although numerous HDACs are expressed and active in bone cells, their tight regulation is critical, as different HDACs exert variant effects on the different cell types (Table 3). For example, expression of HDACs 2, 4, 5, 6, and 7 is normally increased during osteogenesis [186,187,188,189,190,191], and deletion/inhibition of HDACs 2, 3, 4, 7, and 5/9 is associated with decreased BMD or altered bone structure [192,193,194,195,196,197,198,199,200,201,202,203,204]. A genome-wide association study even identified HDAC5 as one of 20 loci associated with osteoporosis [205], representing an independent risk factor for the development of HOD.…”

“…Decreased levels of HDACs 3 and 4 are associated with increased bone catabolism, proposedly mediated via increased expression of FGF-21 and MMPs (e.g., MMP3, MMP10, and MMP13) [196,223,224,225]. Interaction with PTH, often increased during CLD, may alter HDAC4-dependent expression of these genes [225,226,227].…”