Tunable mechanical properties of chitosan-based biocomposite scaffolds for bone tissue engineering applications: A review.

Bone tissue engineering (BTE) aims to develop implantable bone replacements for severe skeletal abnormalities that do not heal. In the field of BTE, chitosan (CS) has become a leading polysaccharide in the development of bone scaffolds. Although CS has several excellent properties, such as biodegradability, biocompatibility, and antibacterial properties, it has limitations for use in BTE because of its poor mechanical properties, increased degradation, and minimal bioactivity. To address these issues, researchers have explored other biomaterials, such as synthetic polymers, ceramics, and CS coatings on metals, to produce CS-based biocomposite scaffolds for BTE applications. These CS-based biocomposite scaffolds demonstrate superior properties, including mechanical characteristics, such as compressive strength, Young's modulus, and tensile strength. In addition, they are compatible with neighboring tissues, exhibit a controlled rate of degradation, and promote cell adhesion, proliferation, and osteoblast differentiation. This review provides a brief outline of the recent progress in making different CS-based biocomposite scaffolds and how to characterize them so that their mechanical properties can be tuned using crosslinkers for bone regeneration.

Crosstalk between Wnt and bone morphogenetic protein signaling during osteogenic differentiation.

Mesenchymal stem cells (MSCs) originate from many sources, including the bone marrow and adipose tissue, and differentiate into various cell types, such as osteoblasts and adipocytes. Recent studies on MSCs have revealed that many transcription factors and signaling pathways control osteogenic development. Osteogenesis is the process by which new bones are formed; it also aids in bone remodeling. Wnt/ß-catenin and bone morphogenetic protein (BMP) signaling pathways are involved in many cellular processes and considered to be essential for life. Wnt/ß-catenin and BMPs are important for bone formation in mammalian development and various regulatory activities in the body. Recent studies have indicated that these two signaling pathways contribute to osteogenic differentiation. Active Wnt signaling pathway promotes osteogenesis by activating the downstream targets of the BMP signaling pathway. Here, we briefly review the molecular processes underlying the crosstalk between these two pathways and explain their participation in osteogenic differentiation, emphasizing the canonical pathways. This review also discusses the crosstalk mechanisms of Wnt/BMP signaling with Notch- and extracellular-regulated kinases in osteogenic differentiation and bone development.

Current approaches in tissue engineering-based nanotherapeutics for osteosarcoma treatment.

Osteosarcoma (OS) is a malignant bone neoplasm plagued by poor prognosis. Major treatment strategies include chemotherapy, radiotherapy, and surgery. Chemotherapy to treat OS has severe adverse effects due to systemic toxicity to healthy cells. A possible way to overcome the limitation is to utilize nanotechnology. Nanotherapeutics is an emerging approach in treating OS using nanoparticulate drug delivery systems. Surgical resection of OS leaves a critical bone defect requiring medical intervention. Recently, tissue engineered scaffolds have been reported to provide physical support to bone defects and aid multimodal treatment of OS. These scaffolds loaded with nanoparticulate delivery systems could also actively repress tumor growth and aid new bone formation. The rapid developments in nanotherapeutics and bone tissue engineering have paved the way for improved treatment efficacy for OS-related bone defects. This review focuses on current bifunctional nanomaterials-based tissue engineered (NTE) scaffolds that use novel approaches such as magnetic hyperthermia, photodynamic therapy, photothermal therapy, bioceramic and polymeric nanotherapeutics against OS. With further optimization and screening, NTE scaffolds could meet clinical applications for treating OS patients.

Nuciferine-loaded chitosan hydrogel-integrated 3D-printed polylactic acid scaffolds for bone tissue engineering: A combinatorial approach.

Critical-sized bone defects resulting from severe trauma and open fractures cannot spontaneously heal and require surgical intervention. Limitations of traditional bone grafting include immune rejection and demand-over-supply issues leading to the development of novel tissue-engineered scaffolds. Nuciferine (NF), a plant-derived alkaloid, has excellent therapeutic properties, but its osteogenic potential is yet to be reported. Furthermore, the bioavailability of NF is obstructed due to its hydrophobicity, requiring an efficient drug delivery system, such as chitosan (CS) hydrogel. We designed and fabricated polylactic acid (PLA) scaffolds via 3D printing and integrated them with NF-containing CS hydrogel to obtain the porous biocomposite scaffolds (PLA/CS-NF). The fabricated scaffolds were subjected to in vitro physicochemical characterization, cytotoxicity assays, and osteogenic evaluation studies. Scanning electron microscopic studies revealed uniform pore size distribution on PLA/CS-NF scaffolds. An in vitro drug release study showed a sustained and prolonged release of NF. The cyto-friendly nature of NF in PLA/CS-NF scaffolds towards mouse mesenchymal stem cells (mMSCs) was observed. Also, cellular and molecular level studies signified the osteogenic potential of NF in PLA/CS-NF scaffolds on mMSCs. These results indicate that the PLA/CS-NF scaffolds could promote new bone formation and have potential applications in bone tissue engineering.

Role and architectural significance of porous chitosan-based scaffolds in bone tissue engineering.

In designing and fabricating scaffolds to fill the bone defects and stimulate new bone formation, the biomimetics of the construct is a crucial factor in invoking the bone microenvironment to promote osteogenic differentiation. Regarding structural traits, changes in porous characteristics of the scaffolds, such as pore size, pore morphology, and percentage porosity, may patronize or jeopardize their other physicochemical and biological properties. Chitosan (CS), a biodegradable naturally occurring polymer, has recently drawn considerable attention as a scaffolding material in tissue engineering and regenerative medicine. CS-based microporous scaffolds have been reported to aid osteogenesis under both in vitro and in vivo conditions by supporting cellular attachment and proliferation of osteoblast cells and the formation of mineralized bone matrix. This related notion may be found in numerous earlier research, even though the precise mechanism of action that encourages the development of new bone still needs to be understood completely. This article presents the potential correlations and the significance of the porous properties of the CS-based scaffolds to influence osteogenesis and angiogenesis during bone regeneration. This review also goes over resolving the mechanical limitations of CS by blending it with other polymers and ceramics.

Nanogels for bone tissue engineering - from synthesis to application.

Nanogels are cross-linked hydrogel nanoparticles with a three-dimensional, tunable porous structure that merges the best features of hydrogels and nanoparticles, including the ability to retain their hydrated nature and to swell and shrink in response to environmental changes. Nanogels have attracted increasing attention for use in bone tissue engineering as scaffolds for growth factor transport and cell adhesion. Their three-dimensional structures allow the encapsulation of a wide range of hydrophobic and hydrophilic drugs, enhance their half-life, and impede their enzymatic breakdown in vivo. Nanogel-based scaffolds are a viable treatment modality for enhanced bone regeneration. They act as carriers for cells and active ingredients capable of controlled release, enhanced mechanical support, and osteogenesis for enhanced bone tissue regeneration. However, the development of such nanogel constructs might involve combinations of several biomaterials to fabricate active ingredients that can control release, enhance mechanical support, and facilitate osteogenesis for more effective bone tissue regeneration. Hence, this review aims to highlight the potential of nanogel-based scaffolds to address the needs of bone tissue engineering.

Recent Advancements in Electrospun Chitin and Chitosan Nanofibers for Bone Tissue Engineering Applications.

Treatment of large segmental bone loss caused by fractures, osteomyelitis, and non-union results in expenses of around USD 300,000 per case. Moreover, the worst-case scenario results in amputation in 10% to 14.5% of cases. Biomaterials, cells, and regulatory elements are employed in bone tissue engineering (BTE) to create biosynthetic bone grafts with effective functionalization that can aid in the restoration of such fractured bones, preventing amputation and alleviating expenses. Chitin (CT) and chitosan (CS) are two of the most prevalent natural biopolymers utilized in the fields of biomaterials and BTE. To offer the structural and biochemical cues for augmenting bone formation, CT and CS can be employed alone or in combination with other biomaterials in the form of nanofibers (NFs). When compared with several fabrication methods available to produce scaffolds, electrospinning is regarded as superior since it enables the development of nanostructured scaffolds utilizing biopolymers. Electrospun nanofibers (ENFs) offer unique characteristics, including morphological resemblance to the extracellular matrix, high surface-area-to-volume ratio, permeability, porosity, and stability. This review elaborates on the recent strategies employed utilizing CT and CS ENFs and their biocomposites in BTE. We also summarize their implementation in supporting and delivering an osteogenic response to treat critical bone defects and their perspectives on rejuvenation. The CT- and CS-based ENF composite biomaterials show promise as potential constructions for bone tissue creation.

Antiproliferative and Apoptotic Effects of pH-Responsive Veratric Acid-Loaded Polydopamine Nanoparticles in Human Triple Negative Breast Cancer Cells.

Veratric acid (VA) is plant-derived phenolic acid known for its therapeutic potential, but its anticancer effect on highly invasive triple-negative breast cancer (TNBC) is yet to be evaluated. Polydopamine nanoparticles (nPDAs) were chosen as the drug carrier to overcome VA's hydrophobic nature and ensure a sustained release of VA. We prepared pH-sensitive nano-formulations of VA-loaded nPDAs and subjected them to physicochemical characterization and in vitro drug release studies, followed by cell viability and apoptotic assays on TNBC cells (MDA-MB-231 cells). The SEM and zeta analysis revealed spherical nPDAs were uniform size distribution and good colloidal stability. In vitro drug release from VA-nPDAs was sustained, prolonged and pH-sensitive, which could benefit tumor cell targeting. MTT and cell viability assays showed that VA-nPDAs (IC50=17.6 µM) are more antiproliferative towards MDA-MB-231 cells than free VA (IC50=437.89 µM). The induction of early and late apoptosis by VA-nPDAs in the cancer cells was identified using annexin V and dead cell assay. Thus, the pH response and sustained release of VA from nPDAs showed the potential to enter the cell, inhibit cell proliferation, and induce apoptosis in human breast cancer cells, indicating the anticancer potential of VA.

Bioactive Molecule-incorporated Polymeric Electrospun Fibers for Bone Tissue Engineering.

Bone tissue engineering (BTE) is based on the participation and combination of different biomaterials, cells, and bioactive molecules to generate biosynthetic grafts for bone regeneration. Electrospinning has been used to fabricate fibrous scaffolds, which provide nanoscale architecture comprising interconnecting pores, resembling the natural hierarchy of tissues and enabling the formation of artificial functional tissues. Electrospun fibers for BTE applications have been mostly produced from polymers (chitosan, alginate, polycaprolactone, polylactic acid) and bioceramics (hydroxyapatite). Stem cells are among the most prolific cell types employed in regenerative medicine owing to their self-renewal and differentiation capacity. Most importantly, bioactive molecules, such as synthetic drugs, growth factors, and phytocompounds, are consistently used to regulate cell behavior inducing differentiation towards the osteoblast lineage. An expanding body of literature has provided evidence that these electrospun fibers loaded with bioactive molecules support the differentiation of stem cells towards osteoblasts. Thus, this review briefly describes the current development of polymers and bioceramic-based electrospun fibers and the influence of bioactive molecules in these electrospun fibers on bone tissue regeneration.

Identification and characterization of TGF-ß1-responsive Runx2 acetylation sites for matrix Metalloproteinase-13 expression in osteoblastic cells.

In skeletal tissues, transforming growth factor-beta 1 (TGF-ß1) serves a number of activities. For example, in osteoblastic cells, TGF-ß1 stimulates the expression of matrix metalloproteinase-13 (MMP-13, a bone remodeling gene), which requires the bone transcription factor Runx2. Although TGF-ß1 is known to stimulate Runx2 acetylation, the sites involved in MMP-13 gene activation remain unknown. Mass spectrometry analysis revealed that Runx2 was acetylated at one site (K134) and three sites (K24, K134, and K169) following control and TGF-ß1-treatment, respectively, in osteoblastic cells. In addition, we mutated the lysine residues in the Runx2 construct into arginine and transfected the construct into mouse mesenchymal stem cells (C3H10T1/2). Wild-type Runx2 expression and acetylation were significantly increased by TGF-ß1-treatment, whereas this effect was decreased in the presence of the Runx2 double mutant construct (K24 + K169) in C3H10T1/2 cells. TGF-ß1 enhanced MMP-13 promoter activity in cells transfected with the wild-type Runx2 construct, but this effect was considerably reduced in cells transfected with the Runx2 double mutant construct (K24 + K169), according to a luciferase reporter test. Hence, the stability of Runx2 may be mediated by TGF-ß1-induced acetylation at K24 and K169 and is required for MMP-13 expression in osteoblastic cells. These findings add to our knowledge of TGF-ß1, Runx2, and MMP-13's physiological roles in bone metabolism.

Angiogenic and osteogenic effects of flavonoids in bone regeneration.

Bone is a highly vascularized tissue that relies on a close spatial and temporal interaction between blood vessels and bone cells. As a result, angiogenesis is critical for bone formation and healing. The vascular system supports bone regeneration by delivering oxygen, nutrients, and growth factors, as well as facilitating efficient cell-cell contact. Most clinical applications of engineered bone grafts are hampered by insufficient vascularization after implantation. Over the last decade, a number of flavonoids have been reported to have osteogenic-angiogenic potential in bone regeneration because of their excellent bioactivity, low cost, availability, and minimal in vivo toxicity. During new bone formation, the osteoinductive nature of certain flavonoids is involved in regulating multiple signaling pathways contributing toward the osteogenic-angiogenic coupling. This review briefly outlines the osteogenic-angiogenic potential of those flavonoids and the mechanisms of their action in promoting bone regeneration. However, further studies are needed to investigate their delivery strategies and establish their clinical efficacy.

Regulation of transforming growth factor-ß1-stimulation of Runx2 acetylation for matrix metalloproteinase 13 expression in osteoblastic cells.

Transforming growth factor beta 1 (TGF-ß1) functions as a coupling factor between bone development and resorption. Matrix metalloproteinase 13 (MMP13) is important in bone remodeling, and skeletal dysplasia is caused by a deficiency in MMP13 expre-ssion. Runx2, a transcription factor is essential for bone development, and MMP13 is one of its target genes. TGF-ß1 promoted Runx2 phosphorylation, which was necessary for MMP13 production in osteoblastic cells, as we previously shown. Since the phosphorylation of some proteins causes them to be degraded by the ubiquitin/proteasome pathway, we hypothesized that TGF-ß1 might stabilize the phosphorylated Runx2 protein for its activity by other post-translational modification (PTM). This study demonstrated that TGF-ß1-stimulated Runx2 acetylation in rat osteoblastic cells. p300, a histone acetyltransferase interacted with Runx2, and it promoted Runx2 acetylation upon TGF-ß1-treatment in these cells. Knockdown of p300 decreased the TGF-ß1-stimulated Runx2 acetylation and MMP13 expression in rat osteoblastic cells. TGF-ß1-treatment stimulated the acetylated Runx2 bound at the MMP13 promoter, and knockdown of p300 reduced this effect in these cells. Overall, our studies identified the transcriptional regulation of MMP13 by TGF-ß1 via Runx2 acetylation in rat osteoblastic cells, and these findings contribute to the knowledge of events presiding bone metabolism.

Advancements in nucleic acids-based techniques for bone regeneration.

The dynamic biology of bone involving an enormous magnitude of cellular interactions and signaling transduction provides ample biomolecular targets, which can be enhanced or repressed to mediate a rapid regeneration of the impaired bone tissue. The delivery of nucleic acids such as DNA and RNA can enhance the expression of osteogenic proteins. Members of the RNA interference pathway such as miRNA and siRNA can repress negative osteoblast differentiation regulators. Advances in nanomaterials have provided researchers with a plethora of delivery modules that can ensure proper transfection. Combining the nucleic acid carrying vectors with bone scaffolds has met with tremendous success in accomplishing bone formation. Recent years have witnessed the advent of CRISPR and DNA nanostructures in regenerative medicine. This review focuses on the delivery of nucleic acids and touches upon the prospect of CRISPR and DNA nanostructures for bone tissue engineering, emphasizing their potential in treating bone defects.

Three-dimensional-poly(lactic acid) scaffolds coated with gelatin/magnesium-doped nano-hydroxyapatite for bone tissue engineering.

BACKGROUND: Treatment of critical-sized bone defects has progressively evolved over the years from metallic implants to more ingenious three-dimensional-based scaffolds. The use of three-dimensional scaffolds for bone regeneration from biodegradable polymers like poly(lactic acid) (PLA) is gaining popularity. Scaffolds with surface functionalization using gelatin (Gel) have the advantages of biocompatibility and cell adhesion. Nano-hydroxyapatite (nHAp) is one of the most promising implant materials utilized in orthopaedics. The osteogenic potential of the nHAp can be improved by the substitution of magnesium (Mg) ions onto the crystal lattice of nHAp. Thus, the goal of this work was to make three-dimensional-PLA scaffolds covered with Gel/Mg-nHAp for osteogenic effect. METHODS AND RESULTS: The designed three-dimensional-PLA/Gel/Mg-nHAp scaffolds were attributed to various characterizations for the examination of their physicochemical, mechanical properties, cyto-compatibility, and biodegradability as well as their ability to promote osteogenesis in vitro. Mouse mesenchymal stem cells (mMSCs) were cytocompatible with these scaffolds. The osteogenic potential of three-dimensional-PLA/Gel/Mg-nHAp scaffolds employing mMSCs was validated at the cellular and molecular levels. The three-dimensional-PLA/Gel/Mg-nHAp scaffolds stimulated the differentiation of mMSCs towards osteoblastic lineage. CONCLUSION: Based on these findings, we suggest that the three-dimensional-PLA/Gel/Mg-nHAp scaffolds' osteogenic capability may be advantageous in the mending of bone defects in orthopedic applications.

Polycaprolactone fibrous electrospun scaffolds reinforced with copper doped wollastonite for bone tissue engineering applications.

The bone defects healing are always associated with post implantation infections; hence biomaterials rules significant role for orchestration of defective bone. In this study, we synthesized biocomposite scaffold by combining polycaprolactone (PCL), wollastonite (Ws) and metal ions (Cu) by electrospinning technique. The manufactured scaffolds (PCL/Ws andPCL/Cu-Ws) were subjected to physio-chemical characterization by scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier Transform Infra Red Spectroscopy (FTIR) and XRD. The surface topography of the scaffolds was found to be micro-fibrous in nature and each fiber was cylindrical in structure. The exogenous biomineralization and protein adsorption capacity of these scaffolds were studied. Enhanced amount of protein was adsorbed on PCL/Cu-Ws than PCL/Ws scaffold after incubating for 48 hr in foetal bovine serum (FBS) also the biomineralization shown to be promoted the apatite formation in vitro. The synthesized PCL/Cu-Ws scaffold was biocompatible to mouse mesenchymal stem cells and enhanced the mRNA expressionof osteoblastic specific marker genes including alkaline phosphatase and type I collagen and major transcription factor Runx2 in the presence of osteogenic medium indicates the osteoconductive nature of the scaffolds. The amount of calcium deposition and promotion of osteoblast differentiation and mineralization on human osteoblast cells was confirmed by alizarin red staining. The fabricated scaffolds possess potent antibacterial effect against Staphylococcu aureus and Escherichia coli. Hence, our outcomes confirmed that the PCL/Ws and PCL/Cu-Ws scaffolds promote bonesynthesis by cell proliferation and differentiation suitable for applications in bone regeneration orbone defects.

Valproic acid, A Potential Inducer of Osteogenesis in Mouse Mesenchymal Stem Cells.

BACKGROUND: Recent reports have unveiled the potential of flavonoids to enhance bone formation and assuage bone resorption due to their involvement in cell signaling pathways. They also act as an effective alternative to circumvent the disadvantages associated with existing treatment methods, which has increased their scope in orthopedic research. Valproic acid (VA, 2-propylpentanoic acid) is one such flavonoid, obtained from an herbaceous plant, used in the treatment of epilepsy and various types of seizures. OBJECTIVE: In this study, the role of VA in osteogenesis and the molecular mechanisms underpinning its action in mouse mesenchymal stem cells (mMSCs) were determined. METHODS: Results: Cytotoxic studies validated VA's amiable nature in mMSCs. Alizarin red and von Kossa staining results showed an increased deposition of calcium phosphate in VA-treated mMSCs, which confirmed the occurrence of osteoblast differentiation and mineralization at a cellular level. At the molecular level, there were increased levels of expression of Runx2, a vital bone transcription factor, and other major osteoblast differentiation marker genes in the VA-treated mMSCs. Further, VA-treatment in mMSCs upregulated mir-21 and activated the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway, which might be essential for the expression/activity of Runx2. CONCLUSION: Thus, the current study confirmed the osteoinductive nature of VA at the cellular and molecular levels, opening the possibility for its application in bone therapeutics with mir-21.

Regulation of Runx2 and Its Signaling Pathways by MicroRNAs in Breast Cancer Metastasis.

As a major threat among women globally, breast cancer (BC) emerges as a primary research focus for several researchers. Although various therapeutic regimens are available, there is an increased chance of metastasis of BC cells, which raises the severity of this malignancy. Of multiple preferred secondary targets, metastasis to bone is extensively studied. Besides deemed as a bone transcription factor, Runx2 also acts as a metastatic factor that promotes growth and metastasis of BC cells. Studies have reported the significant role of microRNAs (miRNAs) in BC pathogenesis and metastasis by governing Runx2 expression. Additionally, dysregulation of the signaling pathways, including Wnt/ß-catenin, TGF-ß, Notch, and PI3K/AKT, has been observed to influence the expression of Runx2 in BC cells. In this review, we have aimed to highlight the regulatory role of miRNAs in targeting Runx2 both directly and indirectly by governing respective signaling pathways during bone metastasis of BC.

Regulation of Breast Cancer Progression by Noncoding RNAs.

BACKGROUND: Breast cancer (BC) is the cardinal cause of cancer-related deaths among women across the globe. Our understanding of the molecular mechanisms underlying BC invasion and metastasis remains insufficient. Recent studies provide compelling evidence on the prospective contribution of noncoding RNAs (ncRNAs) and the association of different interactive mechanisms between these ncRNAs with breast carcinogenesis. MicroRNAs (small ncRNAs) and lncRNAs (long ncRNAs) have been explored extensively as classes of ncRNAs in the pathogenesis of several malignancies, including BC. OBJECTIVE: In this review, we aim to provide a better understanding of the involvement of miRNAs and lncRNAs and their underlying mechanisms in BC development and progression that may assist the development of monitoring biomarkers and therapeutic strategies to effectively combat BC. CONCLUSION: These ncRNAs play critical roles in cell growth, cell cycle regulation, epithelialmesenchymal transition (EMT), invasion, migration, and apoptosis among others, and were observed to be highly dysregulated in several cancers. The miRNAs and lncRNAs were observed to interact with each other through several mechanisms that governed the expression of their respective targets and could act either as tumor suppressors or as oncogenes, playing a crucial part in breast carcinogenesis.

Biodistribution and pharmacokinetics of thiolated chitosan nanoparticles for oral delivery of insulin in vivo.

To improve the quality of life of diabetic patients, oral delivery of insulin would be better than subcutaneous injection, and the encapsulation of insulin for its oral delivery is a promising alternative one. In this study, we prepared an oral insulin delivery system using thiolated chitosan nanoparticles (TCNPs) loaded with insulin (Ins) and tested under in vitro and in vivo systems. TCNPs prepared from CS and pentaerythritol tetrakis (3-mercaptopropionate) (PETMP) at 4:1 ratio showed 220 ± 4 nm, 2.3 ± 1 mV, and 119 ± 4 µmol g-1 in their size, charge and sulfhydryl content, respectively. There was a sustained release of insulin from the TCNPs at pH 5.3. TCNPs treatment did not alter cell viability in vitro and oral administration of TCNPs reached over the tip of the microvilli near the intestinal mucosa in vivo. There were increased and decreased the levels of insulin and glucose in the blood, respectively when Ins-TCNPs were orally administered in the diabetes induced rats. Thus, our results suggested that the insulin stays significantly for a prolonged period to make bio-distribution and bioavailability due to its interaction with the mucus of the intestine, thus offering a better oral insulin delivery system for diabetic patients.

miR-873-3p targets HDAC4 to stimulate matrix metalloproteinase-13 expression upon parathyroid hormone exposure in rat osteoblasts.

Matrix metalloproteinase-13 (MMP-13) plays a predominant role in endochondral bone formation and bone remodeling. Parathyroid hormone (PTH) stimulates the expression of MMP-13 via Runx2, a bone transcription factor in rat osteoblastic cells (UMR106-01), and histone deacetylase 4 (HDAC4) acts as a corepressor of Runx2. Moreover, microRNAs (miRNAs) play an important role in regulating genes posttranscriptionally. Here, we hypothesized that PTH upregulates the miRNAs targeting HDAC4, which could lead to increased Runx2 activity and MMP-13 expression in rat osteoblastic cells. We identified several miRNAs that putatively target rat HDAC4 using bioinformatics tools. miR-873-3p was significantly upregulated by PTH in rat osteoblasts. miR-873-3p overexpression downregulated HDAC4 protein expression, increased Runx2 binding at the MMP-13 promoter, and increased MMP-13 messenger RNA expression in UMR106-01 cells. A luciferase reporter assay identified the direct targeting of miR-873-3p at the 3'-untranslated region of HDAC4. Thus, miR-873-3p targeted HDAC4 and relieved the corepressor effect of HDAC4 on Runx2 for MMP-13 expression in rat osteoblasts. This study advances our knowledge of posttranscriptional gene regulation occurring in bone and bone-related diseases and clarifies the role of miRNAs as diagnostic biomarkers.