The efficacy of combining adjuvants with non-surgical periodontal therapy in individuals with type 2 diabetes: A Bayesian network meta-analysis.

AIM: This Bayesian network meta-analysis of randomized controlled trials assessed the effect of adjuvant periodontal treatment in both periodontal and HbA1c outcomes in adult individuals with type 2 diabetes (T2DM). MATERIALS AND METHODS: A systematic search was done up to February 2023 comparing sub-gingival debridement (SD) in combination with local or systemic adjuvant treatment with SD alone for individuals with T2DM. The primary outcomes were changes in absolute HbA1c levels and full-mouth probing depth reported at 3- to 6-month post-treatment. RESULTS: Seventy-two eligible publications evaluating 27 adjuvant treatments were retrieved. The combination of SD and systemic antibiotic metronidazole or SD and antioxidant alpha lipoic acid provided, respectively, 1.4% (95% credible interval [CrI] 0.48; 2.20) and 2.4% (95% CrI 1.50; 3.30) more significant improvement on HbA1c levels, and 0.89 mm (95% CrI 0.23; 1.50) and 0.92 mm (95% CrI 0.02; 0.92) greater periodontal probing depth reductions. Other adjuvant treatments provided added benefit to the periodontal outcomes without discernible effects on HbA1c. CONCLUSIONS: Adjuvant use of metronidazole or alpha lipoic acid was the best adjunct option to provide clinically meaningful HbA1c levels and probing depth reductions. However, no strong recommendation can be drawn due to the scarcity of studies for each adjuvant treatment and the low certainty of the resultant evidence.

Systemic Dietary Hesperidin Modulation of Osteoclastogenesis, Bone Homeostasis and Periodontal Disease in Mice.

This study aimed to evaluate the effects of hesperidin (HE) on in vitro osteoclastogenesis and dietary supplementation on mouse periodontal disease and femoral bone phenotype. RAW 264.7 cells were stimulated with RANKL in the presence or absence of HE (1, 100 or 500 µM) for 5 days, and evaluated by TRAP, TUNEL and Western Blot (WB) analyses. In vivo, C57BL/6 mice were given HE via oral gavage (125, 250 and 500 mg/kg) for 4 weeks. A sterile silk ligature was placed between the first and second right maxillary molars for 10 days and microcomputed tomography (µCT), histopathological and immunohistochemical evaluation were performed. Femoral bones subjected or not to dietary HE (500 mg/kg) for 6 and 12 weeks were evaluated using µCT. In vitro, HE 500 µM reduced formation of RANKL-stimulated TRAP-positive(+) multinucleated cells (500 µM) as well as c-Fos and NFATc1 protein expression (p < 0.05), markers of osteoclasts. In vivo, dietary HE 500 mg/kg increased the alveolar bone resorption in ligated teeth (p < 0.05) and resulted in a significant increase in TRAP+ cells (p < 0.05). Gingival inflammatory infiltrate was greater in the HE 500 mg/kg group even in the absence of ligature. In femurs, HE 500 mg/kg protected trabecular and cortical bone mass at 6 weeks of treatment. In conclusion, HE impaired in vitro osteoclastogenesis, but on the contrary, oral administration of a high concentration of dietary HE increased osteoclast numbers and promoted inflammation-induced alveolar bone loss. However, HE at 500 mg/kg can promote a bone-sparing effect on skeletal bone under physiological conditions.

Hesperidin Promotes Osteogenesis and Modulates Collagen Matrix Organization and Mineralization In Vitro and In Vivo.

This study evaluated the direct effect of a phytochemical, hesperidin, on pre-osteoblast cell function as well as osteogenesis and collagen matrix quality, as there is little known about hesperidin's influence in mineralized tissue formation and regeneration. Hesperidin was added to a culture of MC3T3-E1 cells at various concentrations. Cell proliferation, viability, osteogenic gene expression and deposited collagen matrix analyses were performed. Treatment with hesperidin showed significant upregulation of osteogenic markers, particularly with lower doses. Mature and compact collagen fibrils in hesperidin-treated cultures were observed by picrosirius red staining (PSR), although a thinner matrix layer was present for the higher dose of hesperidin compared to osteogenic media alone. Fourier-transform infrared spectroscopy indicated a better mineral-to-matrix ratio and matrix distribution in cultures exposed to hesperidin and confirmed less collagen deposited with the 100-µM dose of hesperidin. In vivo, hesperidin combined with a suboptimal dose of bone morphogenetic protein 2 (BMP2) (dose unable to promote healing of a rat mandible critical-sized bone defect) in a collagenous scaffold promoted a well-controlled (not ectopic) pattern of bone formation as compared to a large dose of BMP2 (previously defined as optimal in healing the critical-sized defect, although of ectopic nature). PSR staining of newly formed bone demonstrated that hesperidin can promote maturation of bone organic matrix. Our findings show, for the first time, that hesperidin has a modulatory role in mineralized tissue formation via not only osteoblast cell differentiation but also matrix organization and matrix-to-mineral ratio and could be a potential adjunct in regenerative bone therapies.

Evidence of biglycan structure-function in bone homeostasis and aging.

Purpose: Biglycan is a proteoglycan of the small leucine-rich repeat family. It is present in all connective tissues and plays key structural and signaling roles. This review aimed to compile available evidence in the characteristics and distribution of biglycan and its glycosylated and non-glycosylated forms in connective tissues with a specific focus on the contribution to homeostasis of bone and changes of biglycan structure with aging.Methods: The Pubmed database was searched and included the terms "biglycan", "proteoglycans", "glycosaminoglycans", "bone", "osteoblast", "osteocyte", "osteoclast", "aging", "inflammation", "cartilage". Abstracts were appraised and a series of original articles and reviews studied to generate this narrative review.Results: Based on the search, biglycan significantly affects bone development and homeostasis and can be significantly changed by the aging process in several connective tissues, which in turn affects the behavior of tissue and cell responses in aged networks. Further, as the understanding of the various forms of biglycan in vivo is expanded and the function of its components in vitro is dissected, this proteoglycan can potentially serve as a therapeutic or biomarker molecule to detect tissue destruction.Conclusions: Biglycan is a key player in skeletal bone homeostasis, and overall, there is more evidence on the role of biglycan in development and less in the adult physiological or diseased young and aged systems. Further understanding of its conformation, degradation peptides and post-translational modifications will be required to understand the role of biglycan in bone maintenance and to support the development of treatments for age-related bone dysfunctions.

Effect of pore size in bone regeneration using polydopamine-laced hydroxyapatite collagen calcium silicate scaffolds fabricated by 3D mould printing technology.

OBJECTIVE: The pore size of the scaffold is a critical factor in repairing large bone defect. Here, we investigated the potential of bone regeneration using novel nanocomposite polydopamine-laced hydroxyapatite collagen calcium silicate (HCCS-PDA) scaffolds with two different pore sizes, 250 and 500 µm. SAMPLES/SETTING: A total of 12 male Sprague-Dawley rats were implanted with HCCS-PDA scaffold with pore size of either 250 or 500 µm into surgically created critical-sized defect (CSD). METHODS: HCCS-PDA scaffolds were fabricated using mould printing technique. The effect of pore size on mechanical strength of the scaffolds was assessed by compression testing. After seeding with rat mesenchymal stem cells (rMSCs), the scaffolds were implanted, and new bone formation was evaluated using microCT and histomorphometric analysis after 8 weeks. RESULTS: MicroCT and histology analysis demonstrated restricted peripheral new bone formation in either dural or periosteal side and limited new bone formation in the 250 µm pore scaffold. Conversely, the 500-µm pore scaffold showed more penetration of new bone into the scaffold and greater bone regeneration in the rat CSD. CONCLUSION: Based on our results, which demonstrated improved new bone formation in 500 µm pores scaffold, we can conclude that effective scaffold pore size that induces osteointegration and bone regeneration is around 500 µm for HCCS-PDA nanocomposite scaffold.

Effect of Phosphorylated Chitosan on Dentin Erosion: An in vitro Study.

The aim of this study was to evaluate the antierosive effect of phosphorylated chitosan in dentin. Bovine dentin specimens were randomly distributed into the following groups: (1) no treatment (NoTx/negative control), (2) phosphate-buffered saline solution (PBS), (3) AmF/NaF/SnCl2 (positive control), (4) 0.5% chitosan solution (Chi), (5) 0.5% neutral phosphorylated (NP)-Chi, and (6) 0.5% alkaline phosphorylated (AP)-Chi. The specimens were submitted to de-remineralization treatment cycles for 5 days: 0.5% citric acid (2 min), remineralizing solution (30 min), and surface treatment according to assigned groups (2 min, 6×/day). The loss of dentin surface was measured by profilometry. Hardness and modulus of elasticity were measured using a nanoindenter equipped with a Berkovich diamond tip. The dentin surface was analyzed by scanning electron microscopy (SEM). The largest loss of dentin was observed in the No Tx and PBS groups (approx. 25 µm). The group treated with AmF/NaF/SnCl2 showed less loss of dentin (67% reduction vs. NoTx and PBS), followed by the groups treated with NP-Chi and AP-Chi (33% reduction), and Chi (18% reduction). Nanohardness and modulus of elasticity were similar in the NoTx and PBS groups, with a small increase in stiffness in all other groups. SEM revealed that the experimental solution of AP-Chi had a favorable effect on maintaining the integrity of collagen fibrils. AmF/NaF/SnCl2 showed a preserved mineralized collagen surface. Further studies are warranted to explore this nontoxic phosphorylated chitosan polymer as an effective agent in the prevention and treatment of dental erosion.

Critical appraisal: Cross-linkers and the dentin matrix.

The formation of a hybrid layer is essential for successful dentin bonding and is achieved by adhesive penetration between exposed collagen fibrils in the demineralized dentin. Incomplete infiltration of the adhesive within the collagen network results in exposed fibrils, which may suffer enzymatic degradation over time. Methods to increase collagen resistance to proteinases (enzymes that degrade proteins) have been studied. One particular approach is to use collagen cross-linking agents that modify collagen through addition of specific or random amino acid linkage between and within its molecules. This Critical Appraisal provides information on the effects of various cross-linkers on dentin collagen stability, dentin properties, and resin-dentin bond strengths, and calls for critical thinking on the potential effects of this therapeutic approach.

Mitigation of BMP-induced inflammation in craniofacial bone regeneration and improvement of bone parameters by dietary hesperidin.

Based on anti-inflammatory and osteogenic properties of hesperidin (HE), we hypothesized its systemic administration could be a cost-effective method of improving BMP-induced bone regeneration. Sprague-Dawley rats were allocated into 4 groups (n = 10/group): a 5-mm critical-sized mandible defect + collagen scaffold or, scaffold + 1 µg of BMP2 with and without dietary HE at 100 mg/kg. HE was administered by oral gavage 4 weeks prior to surgeries until euthanasia at day 7 or 14 post-surgery. The healing tissue within the defect collected at day 7 was subjected to gene expression analysis. Mandibles harvested at day 14 were subjected to microcomputed tomography and histology. HE + BMP2-treated rats had a statistically significant decrease in expression of inflammatory genes compared to BMP2 alone. The high-dose BMP2 alone caused cystic-like regeneration with incomplete defect closure. HE + BMP2 showed virtually complete bone fusion. Collagen fibril birefringence pattern (red color) under polarized light indicated high organization in BMP2-induced newly formed bone (NFB) in HE-supplemented group (p < 0.05). Clear changes in osteocyte lacunae as well as a statistically significant increase in osteoclasts were found around NFB in HE-treated rats. A significant increase in trabecular volume and thickness, and trabecular and cortical density was found in femurs of HE-supplemented rats (p < 0.05). Our findings show, for the first time, that dietary HE has a remarkable modulatory role in the function of locally delivered high-dose BMP2 in bone regeneration possibly via control of inflammation, osteogenesis, changes in osteocyte and osteoclast function and collagen maturation in regenerated and native bone. In conclusion, HE had a significant skeletal bone sparing effect and the ability to provide a more effective BMP-induced craniofacial regeneration.

Mitigation of BMP-induced Inflammation in Craniofacial Bone Regeneration and Improvement of Bone Parameters by Dietary Hesperidin.

Based on anti-inflammatory and osteogenic properties of hesperidin (HE), we hypothesized its systemic administration could be a cost-effective method of improving BMP-induced bone regeneration. Sprague-Dawley rats were allocated into 4 groups (n=10/group): a 5-mm critical-sized mandible defect + collagen scaffold or, scaffold + 1 µg of BMP2 with and without dietary HE at 100 mg/kg. HE was administered by oral gavage 4 weeks prior to surgeries until euthanasia at day 7 or 14. The healing tissue within the defect collected at day 7 was subjected to gene expression analysis. Mandibles harvested at day 14 were subjected to microcomputed tomography and histology. HE+BMP2-treated rats had a statistically significant decrease in expression of inflammatory genes compared to BMP2 alone. The high-dose BMP2 caused cystic-like regeneration with incomplete defect closure. HE+BMP2 showed virtually complete bone fusion. Red collagen fibrils were significantly higher in BMP2-induced newly formed bone (NFB) in HE-supplemented group (p<0.05) indicating high organization. Clear changes in osteocyte lacunae as well as a statistically significant increase in osteoclasts were found around NFB in HE rats. A significant increase in trabecular volume and thickness, and trabecular and cortical density was found in femurs of HE-supplemented rats (p<0.05). Our findings show, for the first time, that dietary HE has a remarkable modulatory role in locally delivered high-dose BMP2-induced bone possibly via control of inflammation, osteogenesis, changes in osteocyte and osteoclast function and collagen maturation in regenerated and native bone. In conclusion, HE has a significant skeletal bone sparing effect and the ability to provide a more effective BMP-induced craniofacial regeneration.

Perception of COVID-19 pandemic restrictions on dental researchers.

BACKGROUND/OBJECTIVES: Historical evidence shows a gender-based disproportionate effect of pandemics across different populations. In 2020, the coronavirus disease 2019 (COVID-19) pandemic began spreading its devastating effects worldwide. The goal of the present study was to investigate the effect of the COVID-19 pandemic on research productivity, work-life arrangements, and mental health of dental professionals worldwide with focus on gender differences. METHODS: A 38-item survey, concerning demographics, career stage, employer support, family structure, mental health, and relationships, was distributed to 7692 active members of the International Association for Dental Research. Bivariate associations between independent variables and the primary outcome variable were tested using Spearman's correlation test. A logistic regression model was used to assess the simultaneous, independent associations between each variable and researcher productivity. RESULTS: A total of 722 responses were obtained, indicating a 9.4% response rate. Higher productivity was reported by male respondents (p = 0.021), and by those in senior career stages (p = 0.001). Institutional support was associated with higher productivity (p < 0.0001). Lower productivity was reported by younger researchers (p = 0.003). Remote work negatively affected productivity (p < 0.0001) and female respondents reported working more hours, regardless of work location (p = 0.004). Poor mental health was associated with low productivity (p < 0.0001). CONCLUSIONS: Our results showed that the COVID-19 pandemic significantly affected dental professionals' perceived productivity and mental health around the globe. Younger individuals and women were disproportionally affected, and institutional support had a significant influence to mitigate effects of the pandemic for dental researchers.

Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds.

UNLABELLED: Current protocols for differentiation of stem cells make use of multiple treatments of soluble signals and/or matrix factors and result typically in partial differentiation to mature cells with under- or overexpression of adult tissue-specific genes. We developed a strategy for rapid and efficient differentiation of stem cells using substrata of biomatrix scaffolds, tissue-specific extracts enriched in extracellular matrix, and associated growth factors and cytokines, in combination with a serum-free, hormonally defined medium (HDM) tailored for the adult cell type of interest. Biomatrix scaffolds were prepared by a novel, four-step perfusion decellularization protocol using conditions designed to keep all collagen types insoluble. The scaffolds maintained native histology, patent vasculatures, and ≈1% of the tissue's proteins but >95% of its collagens, most of the tissue's collagen-associated matrix components, and physiological levels of matrix-bound growth factors and cytokines. Collagens increased from almost undetectable levels to >15% of the scaffold's proteins with the remainder including laminins, fibronectins, elastin, nidogen/entactin, proteoglycans, and matrix-bound cytokines and growth factors in patterns that correlate with histology. Human hepatic stem cells (hHpSCs), seeded onto liver biomatrix scaffolds and in an HDM tailored for adult liver cells, lost stem cell markers and differentiated to mature, functional parenchymal cells in ≈1 week, remaining viable and with stable mature cell phenotypes for more than 8 weeks. CONCLUSION: Biomatrix scaffolds can be used for biological and pharmaceutical studies of lineage-restricted stem cells, for maintenance of mature cells, and, in the future, for implantable, vascularized engineered tissues or organs.

Uncommon pathogens in an immunocompetent host: respiratory isolation of Cunninghamella bertholletiae, Aspergillus niger, Staphylococcus pseudintermedius and adenovirus in a patient with necrotising pneumonia.

We present the unusual case of a 60-year-old immunocompetent woman with chronic obstructive pulmonary disease who developed a necrotising pneumonia with isolation of Cunninghamella bertholletiae, Aspergillus niger, Staphylococcus pseudintermedius and adenovirus. The patient recovered with antimicrobial therapy and supportive care in the intensive care unit. The current literature on diagnosis and treatment of these pathogens is reviewed.

Biomimetic polydopamine-laced hydroxyapatite collagen material orients osteoclast behavior to an anti-resorptive pattern without compromising osteoclasts' coupling to osteoblasts.

Polydopamine-assisted modification for bone substitute materials has recently shown great application potential in bone tissue engineering due to its excellent biocompatibility and adhesive properties. A scaffold material's impact on osteoclasts is equally as important as its impact on osteoblasts when considering tissue engineering for bone defect repair, as healthy bone regeneration requires an orchestrated coupling between osteoclasts and osteoblasts. How polydopamine-functionalized bone substitute materials modulate the activity of osteoblast lineage cells has been extensively investigated, but much less is known about their impact on osteoclasts. Moreover, most of the polydopamine-functionalized materials would need to additionally load a biomolecule to exert the modulation on osteoclast activity. Herein, we demonstrated that our biomimetic polydopamine-laced hydroxyapatite collagen (PDHC) scaffold material, which does not need to load additional bioactive agent, is sufficiently able to modulate osteoclast activity in vitro. First, PDHC showed an anti-resorptive potential, characterized by decreased osteoclast differentiation and resorption capacity and changes in osteoclasts' transcriptome profile. Next, cAMP response element-binding protein (CREB) activity was found to mediate PDHC's anti-osteoclastogenic effect. Finally, although PDHC altered clastokines expression pattern of osteoclasts, as revealed by transcriptomic and secretomic analysis, osteoclasts' coupling to osteoblasts was not compromised by PDHC. Collectively, this study demonstrated the PDHC material orients osteoclast behavior to an anti-resorptive pattern without compromising osteoclasts' coupling to osteoblasts. Such a feature is favorable for the net increase of bone mass, which endows the PDHC material with great application potential in preclinical/clinical bone defect repair.

Effect of Flavonoid Supplementation on Alveolar Bone Healing-A Randomized Pilot Trial.

We investigated the effects of two common dietary supplements on bone healing in dental extraction sockets in humans. In this randomized pilot trial, male subjects took Grape Seed Extract [GSE] or Grapefruit Extract [GFE] starting two weeks prior to dental extraction and maintained this regimen for sixty days after surgery. Extraction sockets were filled with a collagen plug. After 24 h, a socket sample was collected and processed for quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and an 84-gene wound healing assay. Sixty days after tooth extraction, a core of newly formed bone was obtained prior to dental implant placement and processed for histology. qRT-PCR revealed that GFE led to a significant decrease in platelet-derived growth factor and interleukin (IL)1-ß compared to GSE, and a significant decrease in IL-6 and CXCL2 compared to control. GSE led to a significant increase in coagulation factor Von Willebrand and inflammatory marker IL1-ß compared to GFE. WISP1 and CXCL5 were upregulated in both groups. Overall, GFE showed a downregulation of inflammation and GSE led to a decrease in collagen density and increased osteoclasts. This pilot trial highlights the need for further investigation on the mechanism of action of such supplements on bone healing and oral health.

Decellularized pulp matrix as scaffold for mesenchymal stem cell mediated bone regeneration.

Scaffolds that are used for bone repair should provide an adequate environment for biomineralization by mesenchymal stem cells (MSCs). Recently, decellularized pulp matrices (DPM) have been utilized in endodontics for their high regenerative potential. Inspired by the dystrophic calcification on the pulp matrix known as pulp stone, we developed acellular pulp bioscaffolds and examined their potential in facilitating MSCs mineralization for bone defect repair. Pulp was decellularized, then retention of its structural integrity was confirmed by histological, mechanical, and biochemical evaluations. MSCs were seeded and proliferation, osteogenic gene expression, and biomineralization were assessed to verify DPM's osteogenic effects in vitro. MicroCT, energy-dispersive X-ray (EDX), and histological analyses were used to confirm that DPM seeded with MSCs result in greater mineralization on rat critical-sized defects than that without MSCs. Overall, our study proves DPM's potential to serve as a scaffolding material for MSC-mediated bone regeneration for future craniofacial bone tissue engineering.

Global deletion of Optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget's disease.

Genome-wide association studies (GWAS) have identified Optineurin (OPTN) as genetically linked to Paget's disease of the bone (PDB), a chronic debilitating bone remodeling disorder characterized by localized areas of increased bone resorption and abnormal bone remodeling. However, only ~10% of mouse models with a mutation in Optn develop PDB, thus hindering the mechanistic understanding of the OPTN-PDB axis. Here, we reveal that 100% of aged Optn global knockout (Optn-/-) mice recapitulate the key clinical features observed in PDB patients, including polyostotic osteolytic lesions, mixed-phase lesions, and increased serum levels of alkaline phosphatase (ALP). Differentiation of primary osteoclasts ex vivo revealed that the absence of Optn resulted in an increased osteoclastogenesis. Mechanistically, Optn-deficient osteoclasts displayed a significantly decreased type I interferon (IFN) signature, resulting from both defective production of IFNß and impaired signaling via the IFNα/ßR, which acts as a negative feedback loop for osteoclastogenesis and survival. These data highlight the dual roles of OPTN in the type I IFN response to restrain osteoclast activation and bone resorption, offering a novel therapeutic target for PDB. Therefore, our study describes a novel and essential mouse model for PDB and define a key role for OPTN in osteoclast differentiation.

Long-term bond strengths to dentin treated with different re-wetting solutions.

PURPOSE: To evaluate the microtensile bond strengths (microTBS) of two etch-and-rinse one-bottle adhesive systems to air-dried dentin re-wet with different agents. METHODS: 48 bovine teeth were ground flat to 600-grit and were assigned for treatment with either Single Bond or One-Step adhesives. Each group had three subgroups of re-wetting agents: water, Gluma Desensitizer and Aqua-Prep F. The teeth were acid-etched, air-dried for 5 seconds and re-wet with water, Gluma Desensitizer or Aqua-Prep F for 30 seconds and blot dried. Control specimens were prepared using a moist bonding technique. The adhesives were applied and the teeth were restored with Filtek Z250 or Renew composite. After 24 hours in distilled water at 37 degrees C, the teeth were sectioned into 0.7 mm-thick slabs, trimmed, and immediately tested for microTBS or stored for 6 months or 1 year prior to testing. Fracture sites were examined under scanning electron microscope (SEM). Data were evaluated by one- and three-way ANOVA, and Fisher's PLSD test (P<0.05). RESULTS: Except for Aqua-Prep F, the microTBS in the control, water and Gluma Desensitizer subgroups did not change significantly after 1-year for both Single Bond and One-Step groups. SEM analysis showed no specific pattern of fracture in the Single Bond specimens. One-Step had the majority of the fractures at the interface at baseline, and becoming a mixture of fractures at the interface and within the adhesive resin after 1 year.

Identification of the effector domain of biglycan that facilitates BMP-2 osteogenic function.

We have reported that recombinant biglycan (BGN) core protein accelerates bone formation in vivo by enhancing bone morphogenetic protein (BMP)-2 function. The purpose of the present study was to identify the specific domain ("effector") within the BGN core protein that facilitates BMP-2 osteogenic function. Thus, we generated various recombinant and synthetic peptides corresponding to several domains of BGN, and tested their effects on BMP-2 functions in vitro. The results demonstrated that the leucine-rich repeats 2-3 domain (LRR2-3) of BGN significantly enhanced the BMP-2 induced Smad1/5/9 phosphorylation, osteogenic gene expression, and alkaline phosphatase activity in myogenic C2C12 cells. Furthermore, addition of LRR2-3 to osteoblastic MC3T3-E1 cells accelerated in vitro mineralization without compromising the quality of the mineral and matrix. These data indicate that LRR2-3 is, at least in part, responsible for BGN's ability to enhance BMP-2 osteogenic function, and it could be useful for bone tissue regeneration.