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In this work we obtain the pointwise almost everywhere convergence for two families of multilinear operators: (a) truncated homogeneous singular integral operators associated with $L^q$ functions on the sphere and (b) lacunary multiplier operators of limited decay. The a.e. convergence is deduced from the $L^2\times\cdots\times L^2\to L^{2/m}$ boundedness of the associated maximal multilinear operators.

The L p L^p boundedness theory of convolution operators is based on an initial L 2 → L 2 L^2\to L^2 estimate derived from the Fourier transform. The corresponding theory of multilinear operators lacks such a simple initial estimate in view of the unavailability of Plancherel’s identity in this setting, and up to now it has not been clear what a natural initial estimate might be. In this work we obtain initial L 2 × ⋯ × L 2 → L 2 / m L^2\times \cdots \times L^2\to L^{2/m} estimates for three types of important multilinear operators: rough singular integrals, multipliers of Hörmander type, and multipliers whose derivatives satisfy qualitative estimates. These estimates lay the foundation for the derivation of other L p L^p estimates for such operators.

With increased understanding of orthodontic tooth movement (OTM) in recent years, neural regulation of OTM has become an emerging and expanding area of research. Numerous studies have shown that the nervous system, including the central and peripheral systems, regulates bone remodeling through various neuropeptides, receptor expression, etc. OTM is a unique periodontal tissue remodeling process induced by mechanical force, including changes in the periodontal ligament metabolism and alveolar bone remodeling. Various studies have shown that the nervous system participates in the OTM process and regulates the periodontal ligament metabolism. This review summarizes the current researches on neural regulation of bone remodeling and the biological responses within the periodontal ligamentduring OTM under therapeutic loading. We also discuss the issues that remain to be addressed in this field. The exploration of neural regulation on OTM not only assists us to understand the mechanism of OTM more thoroughly, but also provides a new insight to accelerate tooth movement in the future.

Engineering a complete, physiologically functional, periodontal complex structure remains a great clinical challenge due to the highly hierarchical architecture of the periodontium and coordinated regulation of multiple growth factors required to induce stem cell multilineage differentiation. Using biomimetic self-assembly and microstamping techniques, we construct a hierarchical bilayer architecture consisting of intrafibrillarly mineralized collagen resembling bone and cementum, and unmineralized parallel-aligned fibrils mimicking periodontal ligament. The prepared biphasic scaffold possesses unique micro/nano structure, differential mechanical properties, and growth factor-rich microenvironment between the two phases, realizing a perfect simulation of natural periodontal hard/soft tissue interface. The interconnected porous hard compartment with a Young's modulus of 1409.00 ± 160.83 MPa could induce cross-arrangement and osteogenic differentiation of stem cells in vitro, whereas the micropatterned soft compartment with a Young's modulus of 42.62 ± 4.58 MPa containing abundant endogenous growth factors, could guide parallel arrangement and fibrogenic differentiation of stem cells in vitro. After implantation in critical-sized complete periodontal tissue defect, the biomimetic bilayer architecture potently reconstructs native periodontium with the insertion of periodontal ligament fibers into newly formed cementum and alveolar bone by recruiting host mesenchymal stem cells and activating the transforming growth factor beta 1/Smad3 signaling pathway. Taken together, integration of self-assembly and microstamping strategies could successfully fabricate a hierarchical bilayer architecture, which exhibits great potential for recruiting and regulating host stem cells to promote synergistic regeneration of hard/soft tissues., Graphical abstract Image 1, Highlights •A CGF/IMC biphasic scaffold is made by a self-assembly integrated microstamping strategy. •CGF/IMC mimics periodontium in micro/nano structure, mechanics and growth factor environment. •CGF/IMC bidirectionally regulates osteogenic/fibrogenic differentiation of stem cells. •CGF/IMC achieves complete periodontal regeneration by recruiting host stem cells.

We obtain L 2 × L 2 → L 1 L^2\times L^2\to L^1 boundedness for bilinear maximal functions associated with general compact hypersurfaces. Our method is based on the strategy introduced by Barrionuevo et al. [Math. Res. Lett. 25 (2018), pp. 69–1388] and a new multiplier result established by Grafakos, He, and Slavíková [Math. Ann. 376 (2020), pp. 431–455].

We study bilinear rough singular integral operators $\mathcal{L}_{\Omega}$ associated with a function $\Omega$ on the sphere $\mathbb{S}^{2n-1}$. In the recent work of Grafakos, He, and Slav\'ikov\'a (Math. Ann. 376: 431-455, 2020), they showed that $\mathcal{L}_{\Omega}$ is bounded from $L^2\times L^2$ to $L^1$, provided that $\Omega\in L^q(\mathbb{S}^{2n-1})$ for $4/3, Comment: Minor revision. To appear in Math. Ann

Tendon injuries disrupt the balance between stability and mobility, causing compromised functions and disabilities. The regeneration of mature, functional tendons remains a clinical challenge. Here, we perform transcriptional profiling of tendon developmental processes to show that the extracellular matrix-associated protein periostin (Postn) contributes to the maintenance of tendon stem/progenitor cell (TSPC) functions and promotes tendon regeneration. We show that recombinant periostin (rPOSTN) promotes the proliferation and stemness of TSPCs, and maintains the tenogenic potentials of TSPCs in vitro. We also find that rPOSTN protects TSPCs against functional impairment during long-term passage in vitro. For in vivo tendon formation, we construct a biomimetic parallel-aligned collagen scaffold to facilitate TSPC tenogenesis. Using a rat full-cut Achilles tendon defect model, we demonstrate that scaffolds loaded with rPOSTN promote endogenous TSPC recruitment, tendon regeneration and repair with native-like hierarchically organized collagen fibers. Moreover, newly regenerated tendons show recovery of mechanical properties and locomotion functions., The regeneration of functional tendons remains a clinical challenge. Here the authors develop a biomimetic scaffold loaded with recombinant periostin and demonstrate its functionality in promoting tendon stem/progenitor cell recruitment and tenogenic differentiation, and tendon regeneration in a rat full-cut Achilles tendon defect model.

BACKGROUND/AIMS: The importance of identifying the stage of liver fibrosis has motivated the development of non-invasive methods. This study aimed to evaluate the applicability of ultrasound analysis involving the wave-number domain attenuation coefficient (W-Ac) in the non-invasive quantitative differentiation of liver fibrosis. MATERIALS AND METHODS: This was a prospective study of inpatients with hepatitis B–related liver disease treated between October 2016 and January 2018. In ultrasound, the echo from the near-field liver tissue was selected as the reference signal. The W-Ac of liver tissues was based on the fast Fourier transform of the acquired post-beamforming radio frequency signals. These values were compared with fibrosis from biopsy METAVIR score results. A receiver operating characteristic (ROC) curve tested the W-Ac method. RESULTS: A total of 46 patients were enrolled, including 27 males and 19 females. Fibrosis was stage F0 in 12 patients, F1 in 13 patients, F2 in 10 patients, F3 in 7 patients, and F4 in 4 patients. W-Ac increased with the progression of liver fibrosis up to stage F3. There were differences between F0 and F4 stages (p

In this paper, we study dimension-free L p {L^{p}} estimates for UMD lattice-valued q-variations of Hardy–Littlewood averaging operators associated with the Euclidean balls.

Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.

Results analogous to those proved by Rubio de Francia are obtained for a class of maximal functions formed by dilations of bilinear multiplier operators of limited decay. We focus our attention to $L^2\times L^2\to L^1$ estimates. We discuss two applications: the boundedness of the bilinear maximal Bochner-Riesz operator and of the bilinear spherical maximal operator. For the latter we improve the known results by reducing the dimension restriction from $n\ge 8$ to $n\ge 4$., Comment: arXiv admin note: text overlap with arXiv:1607.03527

The host immune response to bone biomaterials is vital in determining scaffold fates and bone regeneration outcomes. The nanometer-scale interface of biomaterials, which independently controls physical inputs to cells, regulates osteogenic differentiation of stem cells and local immune response. Herein, we fabricated biomimetic hierarchical intrafibrillarly mineralized collagen (HIMC) with a bone-like staggered nanointerface and investigated its immunomodulatory properties and mesenchymal stem cell (MSC) recruitment during endogenous bone regeneration. The acquired HIMC potently induced neo-bone formation by promoting CD68+CD163+ M2 macrophage polarization and CD146+STRO-1+ host MSC recruitment in critical-sized bone defects. Mechanistically, HIMC facilitated M2 macrophage polarization and interleukin (IL)-4 secretion to promote MSC osteogenic differentiation. An anti-IL4 neutralizing antibody significantly reduced M2 macrophage-mediated osteogenic differentiation of MSCs. Moreover, HIMC-loaded-IL-4 implantation into critical-sized mandible defects dramatically enhanced bone regeneration and CD68+CD163+ M2 macrophage polarization. The depletion of monocyte/macrophages by clodronate liposomes significantly impaired bone regeneration by HIMC, but did not affect MSC recruitment. Thus, in emulating natural design, the hierarchical nanointerface possesses the capacity to recruit host MSCs and promote endogenous bone regeneration by immunomodulation of macrophage polarization through IL-4.

Objective To examine whether facial reference lines could be used to evaluate the anteroposterior position of the maxillary incisors in patients that had undergone extraction treatment. Methods The study enrolled Angle Class I patients who had favourable facial profiles after extraction treatment. Superimposition of post-treatment lateral photographs and cephalograms were constructed and anatomical landmarks on the forehead were identified. Reference lines of the forehead’s anterior limit line (FALL) and the vertical line through the soft-tissue glabella (G line) were constructed. The distance between the maxillary incisors and the FALL and G line were measured. Regression analyses were performed between the maxillary incisor position and forehead inclination. Results Forty-one patients (31 females and 10 males) were included in the study. The mean ± SD distances of the facial-axis point of the maxillary incisors (FA)–FALL and FA–G line were 1.8 ± 1.9 mm and –2.4 ± 1.8 mm, respectively. The distance of the maxillary incisors to FALL and the relative position of the maxillary incisors were both significantly correlated with forehead inclination. Conclusions The mean position of the maxillary incisors in patients with extraction was approximately in the middle of the G line and the FALL. Correct maxillary incisor position was correlated with forehead inclination.

It is well known that the Hormander smoothness condition sup y ≠ 0 ⁡ ∫ | x | ≥ 2 | y | | K ( x − y ) − K ( x ) | d x ∞ implies weak-type ( 1 , 1 ) estimates for associated L 2 -bounded Calderon–Zygmund operators. It has been an open question to know whether Hormander's condition also suffices to guarantee weak-type ( 1 , 1 , 1 / 2 ) estimates for bilinear Calderon–Zygmund operators that are bounded at one point. In this paper, we provide a negative answer to this question.

Objectives Mechanical force plays an important role in modulating stem cell fate and behaviours. However, how periodontal ligament stem cells (PDLSCs) perceive mechanical stimulus and transfer it into biological signals, and thereby promote alveolar bone remodelling, is unclear. Materials and Methods An animal model of force‐induced tooth movement and a compressive force in vitro was used. After force application, tooth movement distance, mesenchymal stem cell and osteoclast number, and proinflammatory cytokine expression were detected in periodontal tissues. Then, rat primary PDLSCs with or without force loading were isolated, and their stem cell characteristics including clonogenicity, proliferation, multipotent differentiation and immunoregulatory properties were evaluated. Under compressive force in vitro, the effects of the ERK signalling pathway on PDLSC characteristics were evaluated by Western blotting. Results Mechanical force in vivo induced PDLSC proliferation, which was accompanied with inflammatory cytokine accumulation, osteoclast differentiation and TRPV4 activation; the force‐stimulated PDLSCs showed greater clonogenicity and proliferation, reduced differentiation ability, improved induction of macrophage migration, osteoclast differentiation and proinflammatory factor expression. The biological changes induced by mechanical force could be partially suppressed by TRPV4 inhibition. Mechanistically, force‐induced activation of TRPV4 in PDLSCs regulated osteoclast differentiation by affecting the RANKL/OPG system via ERK signalling. Conclusions Taken together, we show here that TRPV4 activation in PDLSCs under mechanical force contributes to changing their stem cell characteristics and modulates bone remodelling during tooth movement., Mechanical force in vivo induced periodontal ligament stem cell proliferation, which was accompanied with inflammatory cytokine accumulation, osteoclast differentiation and TRPV4 activation. The activation of TRPV4 in PDLSCs under mechanical force contributes to the changes in their stem cell characteristics including clonogenicity, proliferation, multipotent differentiation, and immunoregulation and modulates bone remodelling during tooth movement.

Background Tooth movement is a unique bone remodeling process induced by mechanical stimulation. Macrophages are important in mediating inflammatory processes during mechanical load-induced tooth movement. However, how macrophages are regulated under mechanical stimulation remains unclear. Mesenchymal stem cells (MSCs) can modulate macrophage polarization during bone remodeling. Hydrogen sulfide (H2S) can be produced by MSCs and have been linked to bone homeostasis. Therefore, this study aimed to investigate whether H2S contributed to periodontal ligament stem cell (PDLSC)-regulated macrophage polarization and bone remodeling under mechanical stimulation. Methods An experimental mechanical load-induced tooth movement animal model was established. Changes in cystathionine-β-synthase (CBS), markers of M1/M2 macrophages, tooth movement distance, and the number of osteoclasts were examined. The conditioned medium of PDLSCs with or without mechanical loading was utilized to treat THP-1 derived macrophages for 24 h to further investigate the effect of PDLSCs on macrophage polarization. Different treatments with H2S donor, CBS inhibitor, or the inhibitor of STAT1 were used to investigate the related mechanism. Markers of M1/M2 polarization and STAT1 pathway expression were evaluated in macrophages. Results Mechanical load promoted tooth movement and increased the number of M1-like macrophages, M1-associated pro-inflammatory cytokines, and the expression of CBS on the compression side of the periodontal ligament. The injection of CBS inhibitor or H2S donor could further repress or increase the number of M1-like macrophages, tartrate-resistant acid phosphatase-positive osteoclasts and the distance of tooth movement. Mechanistically, load-induced PDLSCs enhanced H2S production, which increased the expression of M1-associated cytokines in macrophages. These effects could be blocked by the administration of CBS inhibitor. Moreover, load-induced H2S steered M1 macrophage polarization via the STAT1 signaling pathway. Conclusions These data suggest a novel mechanism indicating that mechanical load-stimulated PDLSCs produce H2S to polarize macrophages toward the M1 phenotype via the STAT1 signaling pathway, which contributes to bone remodeling and tooth movement process. These results provide new insights into the role of PDLSCs in regulating macrophage polarization and mediating bone remodeling under mechanical stimulation, and indicate that appropriate H2S supplementation may accelerate tooth movement.

Figure S1. H2S concentration in the serum of mice. H2S concentration in the serum increased after GYY4137 administration and decreased after HA administration. *P < 0.05 versus control. #P < 0.05 versus GYY4137.

Figure S2. Representative tartrate-resistant acid phosphatase (TRAP) staining images of the compression side of distal roots. (A) The number of TRAP-positive osteoclasts was upregulated after force was applied, which decreased after HA administration and further enhanced after GYY4137 administration. Large boxed areas show high-magnification views of the small boxed areas. Arrow represents the direction of force. Scale bars: 100 μm. (B) Semiquantification of positive cells. N = 5–6; the positive staining cells were counted in five different slides from each sample. The final result came from the average of three tests. ***P < 0.001 versus control. ###P < 0.001 versus force. &&&P < 0.001 versus force + HA.

Figure S4. Western blot results of THP-1-derived macrophages. (A) No significant changes were observed in TNF-α and arginase-1 expressions in THP-1-induced macrophages after incubated with the supernatant of PDLSCs with or without HA application. (B) No significant changes were observed in TNF-α and arginase-1 expressions in THP-1-derived macrophages after incubated with the supernatant of PDLSCs with or without pSTAT1 inhibitor application. Beta-actin served as the internal control for equal loading. Data represent three independent experiments.

Let H = − Δ + | x | 2 be the Hermite operator in R n . In this paper we study almost everywhere convergence of the Bochner-Riesz means associated with H which is defined by S R λ ( H ) f ( x ) = ∑ k = 0 ∞ ( 1 − 2 k + n R 2 ) + λ P k f ( x ) . Here P k f is the k-th Hermite spectral projection operator. For 2 ≤ p ∞ , we prove that lim R → ∞ ⁡ S R λ ( H ) f = f a.e. for all f ∈ L p ( R n ) provided that λ > λ ( p ) / 2 and λ ( p ) = max ⁡ { n ( 1 / 2 − 1 / p ) − 1 / 2 , 0 } . Conversely, we also show the convergence generally fails if λ λ ( p ) / 2 in the sense that there is an f ∈ L p ( R n ) for 2 n / ( n − 1 ) ≤ p such that the convergence fails. This is in surprising contrast with a.e. convergence of the classical Bochner-Riesz means for the Laplacian. For n ≥ 2 and p ≥ 2 our result tells that the critical summability index for a.e. convergence for S R λ ( H ) is as small as only the half of the critical index for a.e. convergence of the classical Bochner-Riesz means. When n = 1 , we show a.e. convergence holds for f ∈ L p ( R ) with p ≥ 2 whenever λ > 0 . Compared with the classical result due to Askey and Wainger who showed the optimal L p convergence for S R λ ( H ) on R we only need smaller summability index for a.e. convergence.

Figure S5. H2S level in the supernatant of THP-1-derived macrophages. The level of H2S in the culture medium of THP-1-derived macrophages was enhanced or decreased after treated with NaSH or HA. *P < 0.05 versus control. ##P < 0.01 versus NaSH.

OBJECTIVES Temporomandibular joint osteoarthritis (TMJOA) is approximately twice as prevalent in women than in men. Synoviocytes are believed to play a critical role in joint inflammation. However, it is unknown whether synoviocytes from different genders possess sexual dimorphisms that contribute to female-predominant TMJOA. MATERIALS AND METHODS Freund's complete adjuvant combined with monosodium iodoacetate was used to induce TMJOA in female and male rats. Histologic and radiographic features were used to evaluate TMJOA. The expression of CD68, MCP-1, iNOS, and IL-1β was detected by immunohistochemistry and real-time PCR. Primary fibroblast-like synoviocytes (FLSs) isolated from the synovial membrane of female and male rats were used for in vitro experiments. RESULTS Female rats showed aggravated TMJOA features as compared to male rats. Increased expression of iNOS and IL-1β was detected in synovial membrane from female TMJOA rats as compared to male rats. Furthermore, greater amounts of CD68-positive macrophage infiltration and increased MCP-1 expression around the synovial membrane were detected in female TMJOA rats compared to males. Primary cultured FLSs from female rats showed higher sensitivity to TNF-α treatment and recruited increased macrophage migration than male FLSs. More important, ovariectomy (OVX) by ablation in female rats repressed the sensitivity of female FLSs to TNF-α treatment due to the loss of estrogen production. Blockage of the estrogen receptor repressed estrogen-potentiated TNF-α-induced pro-inflammatory cytokine expression in OVX-FLSs. Moreover, the injection of estrogen receptor antagonists relieved the cartilage destruction and bone deterioration of TMJOA in female rats. CONCLUSION Estrogen-sensitized synoviocytes in female rats may contribute to gender differences in the incidence and progression of TMJOA.

Periodontal ligament (PDL), as a mechanical connection between the alveolar bone and tooth, plays a pivotal role in force-induced orthodontic tooth movement (OTM). However, how mechanical force controls remodeling of PDL collagenous extracellular matrix (ECM) is largely unknown. Here, we aimed to evaluate the stress distribution and ECM fiber remodeling of PDL during the process of OTM. An experimental tooth movement model was built by ligating a coil spring between the left maxillary first molar and the central incisors. After activating the coil spring for 7 days, the distance of tooth movement was 0.324 ± 0.021 mm. The 3D finite element modeling showed that the PDL stress obviously concentrated at cervical margin of five roots and apical area of the mesial root, and the compression region was distributed at whole apical root and cervical margin of the medial side (normal stress < −0.05 MPa). After force induction, the ECM fibers were disordered and immature collagen III fibers significantly increased, especially in the apical region, which corresponds to the stress concentration and compression area. Furthermore, the osteoclasts and interleukin-1β expression were dramatically increased in the apical region of the force group. Taken together, orthodontic loading could change the stress distribution of PDL and induce a disordered arrangement and remodeling of ECM fibers. These findings provide orthodontists both mechanical and biological evidences that root resorption is prone to occur in the apical area during the process of OTM.

Introduction Orthodontic tooth movement (OTM) is the core component of orthodontic treatment and is increasingly popular for treating malocclusions. In this study, we aimed to investigate the role of apolipoprotein E (ApoE) in OTM. Methods Thirty patients treated with transmission straight wire technology were selected and longitudinally tracked at 2 different stages of orthodontic treatment (initial 2 months and 12 months of orthodontic treatment). Total saliva was collected and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Western blotting was used to detect the difference in ApoE expression in the saliva samples of the 2 groups. The expression of ApoE was further verified by immunohistochemical staining in a mouse model of tooth movement. Results The results of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry showed significant differences in the components of the salivary peptides in the 2 groups and peptides with a molecular weight of 2010.7 Da were predicted to be ApoE by database analysis. Western blotting further verified a significant difference in the expression of salivary ApoE in the 2 groups. In addition, an OTM model was successfully constructed in mice. The immunohistochemical staining results showed that ApoE expression significantly increased after force loading in the OTM model. Conclusions This study indicated that ApoE participated in and played a role during OTM in patients treated with transmission straight wire technology. This relationship might be related to alveolar bone reconstruction and root resorption. The results provide new ideas for research on the mechanism of tooth movement using precision medicine based on saliva detection.

We establish a weighted inequality for bilinear rough singular integrals with bound controlled by the cube of the characteristic constant of the pair of weights.

We study the rough bilinear singular integral, introduced by Coifman and Meyer , $$ T_\Omega(f,g)(x)=p.v. \! \int_{\mathbb R^{n}}\! \int_{\mathbb R^{n}}\! |(y,z)|^{-2n} \Omega((y,z)/|(y,z)|)f(x-y)g(x-z) dydz, $$ when $\Omega $ is a function in $L^q(\mathbb S^{2n-1})$ with vanishing integral and $2\le q\le \infty$. When $q=\infty$ we obtain boundedness for $T_\Omega$ from $L^{p_1}(\mathbb R^n)\times L^{p_2}(\mathbb R^n)$ to $ L^p(\mathbb R^n) $ when $1, Comment: 23 pages

We use wavelets of tensor product type to obtain the boundedness of bilinear multiplier operators on $$\mathbb R^n\times \mathbb R^n$$ associated with Hormander multipliers on $$\mathbb R^{2n}$$ with minimal smoothness. We focus on the local $$L^2$$ case and we obtain boundedness under the minimal smoothness assumption of n / 2 derivatives. We also provide counterexamples to obtain necessary conditions for all sets of indices.

Hydrogen sulfide (H2S), a gasotransmitter, has been recently linked to mesenchymal stem cell (MSC) function and bone homeostasis. Periodontal ligament stem cells (PDLSCs) are the main MSCs in PDL, which respond to mechanical force to induce physiological activities during orthodontic tooth movement (OTM). However, it is unknown whether mechanical force might induce endogenous H2S production by PDLSCs to regulate alveolar bone homeostasis. Here, we used a mouse OTM model to demonstrate that orthodontic force-induced endogenous H2S production in PDL tissue was associated with macrophage accumulation and osteoclastic activity in alveolar bone. Then, we showed that mechanical force application induced cystathionine β-synthase (CBS) expression and endogenous H2S production by PDLSCs. Moreover, blocking endogenous H2S or systemically increasing H2S levels could decrease or enhance force-induced osteoclastic activities to control tooth movement. We further revealed how force-induced H2S production by PDLSCs contributed to the secretion of monocyte chemoattractant protein-1 (MCP-1) and the expression of receptor activator of nuclear factor–κB ligand/osteoprotegerin (RANKL/OPG) system by PDLSCs. The secretion and expression of these factors controlled macrophage migration and osteoclast differentiation. This study demonstrated that PDLSCs produced H2S to respond to and transduce force signals. Force-induced gasotransmitter H2S production in PDLSCs therefore regulated osteoclastic activities in alveolar bone and controlled the OTM process through the MCP-1 secretion and RANKL/OPG system.

The host immune response to bone biomaterials is vital in determining the fate of scaffolds and also the outcomes of bone regeneration. Mineralized collagen is an ideal tissue-engineering scaffold for bone repair; however, little is known about its immunomodulatory properties after implantation. In this study, extrafibrillarly-mineralized collagen (EMC) and intrafibrillarly-mineralized collagen (IMC) scaffolds with different nanostructures were fabricated and their immunomodulatory properties via macrophage polarization during bone regeneration were investigated. Micro-CT findings showed that the IMC scaffold yielded more new bone formation than the EMC scaffold. In the defect area, more CD68 + CD163 + M2-like macrophages were observed in the IMC group, while M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) increased dramatically in the EMC group. We further demonstrated, from the protein and RNA levels, that M2-associated anti-inflammatory cytokines interleukin (IL)-10 and arginase-1 were highly expressed in the macrophages seeded on the IMC scaffold, while those seeded on the EMC scaffold expressed more M1-related genes iNOS and IL-6. Moreover, the macrophage polarization in response to the nanostructure of mineralized collagen scaffolds influenced the osteogenesis of human bone marrow stromal cells. These findings suggest that the nanostructure of mineralized collagen scaffolds affects macrophage functional polarization during bone regeneration. The immunomodulatory properties of biomaterial scaffolds can be a dictator of bone regeneration outcomes.

The aim of this study was to investigate the roles of CD4