Human salivary histatin‐1 (Hst1) promotes bone morphogenetic protein 2 (BMP2)‐induced osteogenesis and angiogenesis

Abstract

Large‐volume bone defects can result from congenital malformation, trauma, infection, inflammation and cancer. At present, it remains challenging to treat these bone defects with clinically available interventions. Allografts, xenografts and most synthetic materials have no intrinsic osteoinductivity, and so an alternative approach is to functionalize the biomaterial with osteoinductive agents, such as bone morphogenetic protein 2 (BMP2). Because it has been previously demonstrated that human salivary histatin‐1 (Hst1) promotes endothelial cell adhesion, migration and angiogenesis, we examine here whether Hst1 can promote BMP2‐induced bone regeneration. Rats were given subcutaneous implants of absorbable collagen sponge membranes seeded with 0, 50, 200 or 500 μg Hst1 per sample and 0 or 2 μg BMP2 per sample. At 18 days postsurgery, rats were sacrificed, and implanted regional tissue was removed for micro computed tomography (microCT) analyses of new bone (bone volume, trabecular number and trabecular separation). Four samples per group were decalcified and subjected to immunohistochemical staining to analyze osteogenic and angiogenic markers. We observed that Hst1 increased BMP2‐induced new bone formation in a dose‐dependent manner. Co‐administration of 500 μg Hst1 and BMP2 resulted in the highest observed bone volume and trabecular number, the lowest trabecular separation and the highest expression of osteogenic markers and angiogenic markers. Our results suggest that coadministration of Hst1 may enhance BMP2‐induced osteogenesis and angiogenesis, and thus may have potential for development into a treatment for large‐volume bone defects.

Histatin‐1 is a novel osteogenic factor that promotes bone cell adhesion, migration, and differentiation

“…Collectively, our findings uncover a novel role for Histatin-1 in promoting osteoinduction, which paves new avenues to explore its effects in bone regeneration. It should be mentioned that, although the data shown here indicate a moderate osteoinductive effect of Histatin-1, as compared with standard osteoinductive factors, such as BMP-2 (Sun, Shi, Shen et al, 2020), this does not necessarily imply that the performance of Histatin-1 in bone regeneration is moderate or poor at the clinical level. This is because bone regeneration relies on multiple cellular and molecular phenomena regulated in a temporal and spatial manner (Marsell & Einhorn, 2011).…”

“…Interestingly, a more recent study by Sun et al (Sun et al., 2020) showed that Histatin‐1 improves osteoinductive properties of BMP‐2 in a preclinical model. However, that study was conceived on the basis that Histatin‐1 is a proangiogenic factor, but not that the peptide itself was osteoinductive.…”

“…However, that study showed no alterations in ALP activity upon treatment with Histatin‐1 alone, which might be due to the result of brief exposure times or usage of a single cell line. Interestingly, a more recent study showed that Histatin‐1 increases the efficiency of bone morphogenetic protein‐2 (BMP‐2) in inducing ectopic bone formation in vivo (Sun, Shi, Shen et al., 2020), although the mechanisms underlying such effects have not been explored. Consequently, the basic question as to whether Histatin‐1 behaves as a factor that promotes osteogenic differentiation and other bone cell responses, remains unclear.…”

Human Salivary Histatin-1 Promotes Osteogenic Cell Spreading on Both Bio-Inert Substrates and Titanium SLA Surfaces

“…All these data suggest that Hst1 does not enhance osteogenic differentiation, thus bearing no osteoinductivity. On the other hand, in our recent in vivo study, Hst1 significantly promotes angiogenesis and osteogenesis under the stimulation of BMP2 in an ectopic bone induction model (Sun P. et al, 2020). Such an effect of Hst1 on osteogenesis may be attributed to the stimulating effect of Hst1 on angiogenesis (Torres et al, 2017) that favors bone regeneration (Grosso et al, 2017).…”

The multifaceted roles of antimicrobial peptides in oral diseases

“…Among natural antimicrobial peptides, hBDs are expressed in oral bone (Warnke et al, 2006) (Warnke et al, 2013). In addition, hBDs and histatin-1 promoted bone regeneration and prevented infection (Lee et al, 2018;Peng et al, 2020;Sun et al, 2020).…”