Objectives. The role of mechanical stress and transforming growth factor beta 1 (TGF-β1) is important in the initiation and progression of osteoarthritis (OA). However, the underlying molecular mechanisms are not clearly known. Methods. In this study, TGF-β1 from osteoclasts and knee joints were analyzed using a co-cultured cell model and an OA rat model, respectively. Five patients with a femoral neck fracture (four female and one male, mean 73.4 years (68 to 79)) were recruited between January 2015 and December 2015. Results showed that TGF-β1 was significantly upregulated in osteoclasts by cyclic loading in a time- and dose-dependent mode. The osteoclasts were subjected to cyclic loading before being co-cultured with chondrocytes for 24 hours. Results. A significant decrease in the survival rate of co-cultured chondrocytes was found. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay demonstrated that mechanical stress-induced apoptosis occurred significantly in co-cultured chondrocytes but administration of the TGF-β1 receptor inhibitor, SB-505124, can significantly reverse these effects. Abdominal administration of SB-505124 can attenuate markedly articular cartilage degradation in OA rats. Conclusion. Mechanical stress-induced overexpression of TGF-β1 from osteoclasts is responsible for chondrocyte apoptosis and cartilage degeneration in OA. Administration of a TGF-β1 inhibitor can inhibit articular cartilage degradation. Cite this article: R-K. Zhang, G-W. Li, C. Zeng, C-X. Lin, L-S. Huang, G-X. Huang, C. Zhao, S-Y. Feng, H. Fang. Mechanical stress contributes to osteoarthritis development through the activation of transforming growth factor beta 1 (TGF-β1). Bone Joint Res 2018;7:587–594. DOI: 10.1302/2046-3758.711.BJR-2018-0057.R1

Aims. Osteoarthritis (OA) is a common degenerative joint disease. The osteocyte transcriptome is highly relevant to osteocyte biology. This study aimed to explore the osteocyte transcriptome in subchondral bone affected by OA. Methods. Gene expression profiles of OA subchondral bone were used to identify disease-relevant genes and signalling pathways. RNA-sequencing data of a bone loading model were used to identify the loading-responsive gene set. Weighted gene co-expression network analysis (WGCNA) was employed to develop the osteocyte mechanics-responsive gene signature. Results. A group of 77 persistent genes that are highly relevant to extracellular matrix (ECM) biology and bone remodelling signalling were identified in OA subchondral lesions. A loading responsive gene set, including 446 principal genes, was highly enriched in OA medial tibial plateaus compared to lateral tibial plateaus. Of this gene set, a total of 223 genes were identified as the main contributors that were strongly associated with osteocyte functions and signalling pathways, such as ECM modelling, axon guidance, Hippo, Wnt, and transforming growth factor beta (TGF-β) signalling pathways. We limited the loading-responsive genes obtained via the osteocyte transcriptome signature to identify a subgroup of genes that are highly relevant to osteocytes, as the mechanics-responsive osteocyte signature in OA. Based on WGCNA, we found that this signature was highly co-expressed and identified three clusters, including early, late, and persistently responsive genes. Conclusion. In this study, we identified the mechanics-responsive osteocyte signature in OA-lesioned subchondral bone. Cite this article: Bone Joint Res 2022;11(6):362–370

Aims. Proliferation, migration, and differentiation of anterior cruciate ligament (ACL) remnant and surrounding cells are fundamental processes for ACL reconstruction; however, the interaction between ACL remnant and surrounding cells is unclear. We hypothesized that ACL remnant cells preserve the capability to regulate the surrounding cells’ activity, collagen gene expression, and tenogenic differentiation. Moreover, extracorporeal shock wave (ESW) would not only promote activity of ACL remnant cells, but also enhance their paracrine regulation of surrounding cells. Methods. Cell viability, proliferation, migration, and expression levels of Collagen-I (COL-I) A1, transforming growth factor beta (TGF-β), and vascular endothelial growth factor (VEGF) were compared between ACL remnant cells untreated and treated with ESW (0.15 mJ/mm. 2. , 1,000 impulses, 4 Hz). To evaluate the subsequent effects on the surrounding cells, bone marrow stromal cells (BMSCs)’ viability, proliferation, migration, and levels of Type I Collagen, Type III Collagen, and tenogenic gene (Scx, TNC) expression were investigated using coculture system. Results. ESW-treated ACL remnant cells presented higher cell viability, proliferation, migration, and increased expression of COL-I A1, TGF-β, and VEGF. BMSC proliferation and migration rate significantly increased after coculture with ACL remnant cells with and without ESW stimulation compared to the BMSCs alone group. Furthermore, ESW significantly enhanced ACL remnant cells’ capability to upregulate the collagen gene expression and tenogenic differentiation of BMSCs, without affecting cell viability, TGF-β, and VEGF expression. Conclusion. ACL remnant cells modulated activity and differentiation of surrounding cells. The results indicated that ESW enhanced ACL remnant cells viability, proliferation, migration, and expression of collagen, TGF-β, VEGF, and paracrine regulation of BMSC proliferation, migration, collagen expression, and tenogenesis. Cite this article: Bone Joint Res 2020;9(8):457–467

Aims. Developmental dysplasia of the hip (DDH) is a complex musculoskeletal disease that occurs mostly in children. This study aimed to investigate the molecular changes in the hip joint capsule of patients with DDH. Methods. High-throughput sequencing was used to identify genes that were differentially expressed in hip joint capsules between healthy controls and DDH patients. Biological assays including cell cycle, viability, apoptosis, immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were performed to determine the roles of the differentially expressed genes in DDH pathology. Results. More than 1,000 genes were differentially expressed in hip joint capsules between healthy controls and DDH. Both gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that extracellular matrix (ECM) modifications, muscle system processes, and cell proliferation were markedly influenced by the differentially expressed genes. Expression of Collagen Type I Alpha 1 Chain (COL1A1), COL3A1, matrix metalloproteinase-1 (MMP1), MMP3, MMP9, and MMP13 was downregulated in DDH, with the loss of collagen fibres in the joint capsule. Expression of transforming growth factor beta 1 (TGF-β1) was downregulated, while that of TGF-β2, Mothers against decapentaplegic homolog 3 (SMAD3), and WNT11 were upregulated in DDH, and alpha smooth muscle actin (αSMA), a key myofibroblast marker, showed marginal increase. In vitro studies showed that fibroblast proliferation was suppressed in DDH, which was associated with cell cycle arrest in G0/G1 and G2/M phases. Cell cycle regulators including Cyclin B1 (CCNB1), Cyclin E2 (CCNE2), Cyclin A2 (CCNA2), Cyclin-dependent kinase 1 (CDK1), E2F1, cell division cycle 6 (CDC6), and CDC7 were downregulated in DDH. Conclusion. DDH is associated with the loss of collagen fibres and fibroblasts, which may cause loose joint capsule formation. However, the degree of differentiation of fibroblasts to myofibroblasts needs further study. Cite this article: Bone Joint Res 2021;10(9):558–570

Objectives. The injured anterior cruciate ligament (ACL) is thought to exhibit an impaired healing response, and attempts at surgical repair have not been successful. Connective tissue growth factor (CTGF) is reported to be associated with wound healing, probably through transforming growth factor beta 1 (TGF-β1). Methods. A rabbit ACL injury model was used to study the effect of CTGF on ligament recovery. Quantitative real-time PCR (qRT-PCR) was performed for detection of changes in RNA levels of TGF-β1, type 1 collagen (COL1), type 2 collagen (COL2), SRY-related high mobility group-box gene9 (SOX9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metallopeptidase 13 (MMP-13). Expression of related proteins was detected by Western blotting. Results. The current study showed that CTGF could promote the recovery of an injured anterior cruciate ligament. It can upregulate mRNA and expression of TGF-β1, COL1, COL2, SOX9, and tissue inhibitor of TIMP-1, and downregulate mRNA and expression of MMP-13, suggesting that the curative effect of CTGF on injured rabbit ligaments is through regulation of these cellular factors. Conclusions. This finding revealed the healing role of CTGF in injured tissues and provides new possibilities of treating injured tissues and wound healing by using CTGF. Cite this article: X. Sun, W. Liu, G. Cheng, X. Qu, H. Bi, Z. Cao, Q. Yu. The influence of connective tissue growth factor on rabbit ligament injury repair. Bone Joint Res 2017;6:399–404. DOI: 10.1302/2046-3758.67.BJR.2016-0255.R1

Background. Treatment of cartilage defects requires in vitro expansion of human articular chondrocytes (HACs) for autologous chondrocyte implantation (ACI). During standard expansion culture (i.e. plasma osmolarity, 280 mOsm) chondrocytes inevitably lose their specific phenotype (i.e. collagen type II (COL2) expression). This de-differentiation makes them inappropriate for ACI. Physiological osmolarity (i.e. 380 mOsm) improves COL2 expression in vitro, but the underlying reason is unknown. However, an accepted key regulator of chondrocyte differentiation, transforming growth factor beta (TGFβ), is known to stimulate COL2 production. In this study we aimed to elucidate if TGFβ signaling could potentially be driving the COL2 expression under physiological culture conditions. Material and methods. After informed consent was obtained, HACs were isolated from five osteoarthritis (OA) patients and cultured in cytokine-free medium of 280 or 380 mOsm, respectively, under standard 2D in vitro conditions with or without lentiviral TGFβ2 knockdown (RNAi). Expression of TGFβ isoforms, superfamily receptors and chondrocyte marker genes was evaluated by qRT-PCR, TGFβ2 protein secretion by ELISA and TGFβ bioactivity using luciferase reporter assays. Statistical significance was assessed by a student's t-test. Results. TGFβ isoform expression was differentially altered by physiological osmolarity. Specifically, 380 mOsm increased TGFβ2 expression and protein secretion, as well as TGFβ activity. Upon TGFβ2 isoform-specific knockdown COL2 expression was induced. Physiological osmolarity and TGFβ2 RNAi also induced TGFβ1, TGFβ3 and their type I receptor ALK5. Conclusions. We showed that TGFβ2 knockdown increases COL2 expression in human osteoarthritic chondrocytes in vitro, possibly through a regulatory feedback loop involving TGFβ1, TGFβ3 induction and an increased ALK5/ALK1 ratio. This study indicates that TGFβ signalling is involved in osmolarity-induced chondrocyte marker gene expression. Pharmacological targeting of this pathway holds potential to further improve future osmolarity-mediated phenotypic stabilisation in advanced cell-based cartilage repair strategies. Level of Evidence. preclinical. Disclosure. We have nothing to disclose

Complement C5a receptor 1 (C5aR1) has crucial functions in host defense against danger molecules, as does toll-like receptor 2 (TLR2). Both innate immunity receptors interact in immune cells in the context of infectious inflammatory diseases often associated with bone loss, such as periodontitis. C5aR1 plays an important role in bone, as it is expressed on bone cells and strongly upregulated due to bone injury. Importantly, C5aR1-ko mice are protected against arthritis and C5aR1 contributes to bone loss in periodontitis. In contrast, less data exist on the role of TLR2 on osteoblasts, however, it is known that TLR2 is expressed on osteoblasts and contributes to bacterial-induced bone resorption. The aim of this study was to evaluate the interaction of C5aR1 and TLR2 in osteoblasts, including intracellular signaling pathways and gene expression patterns. Primary osteoblasts were isolated from 8–12 week-old WT mice and differentiated for 14 days. Osteoblasts were assessed for expression of C5aR1 and TLR2. Phosphorylation of mitogen-activated protein kinases (MAPK) in response to C5a and Pam3CSK4 (TLR2 agonist) was analyzed by immunoblotting. Gene expression profiling after 30 min and 4 h stimulation of C5a was performed by microarray and candidate genes were validated by quantitative Real-Time PCR (qRT-PCR). Immunoprecipitation was performed using a C5aR1-antibody and C5aR1 and TLR2 were subsequently detected by immunoblotting. Statistics: One way ANOVA p<0.05, n=4–6. We showed that C5aR1 and TLR2 are expressed on osteoblasts and strongly upregulated during differentiation. Via immunoprecipitation, we could show that C5aR1 and TLR2 do physically interact in osteoblasts. We then examined if C5aR1 and TLR2, besides their physical interaction, also act via the same intracellular signaling pathways. Gene expression profiling upon C5a stimulation revealed that the top regulated pathways are related to MAPK and transforming growth factor beta (TGF-β). Respective genes, such as TGF-β (Tgfb1) and its receptor (Tgfbr) were found to be upregulated, and negative MAPK regulators were found to be downregulated, both by microarray analysis and qRT-PCR. Accordingly, we saw a C5aR1- and TLR2-dependent phosphorylation of p38 MAPK. Interestingly, this effect was enhanced and prolonged by costimulation of both receptors. An additive effect of C5aR1 and TLR2 was also seen regarding Cxcl10 levels, which were enhanced compared to C5aR1 or TLR2 stimulation alone. This study shows that C5aR1 and TLR2 interact in osteoblasts, not only physically but also functionally, regarding downstream signaling and target genes. Those data strongly imply a synergistic interplay between the receptors, through which osteoblasts possibly contribute to inflammatory reactions affecting bone

The formation of restrictive adhesions around the musculotendinous unit after injury is one of the most vexing processes faced by the surgeon. In flexor tendons it has been shown that the synovial tissue is the source of aggressive fibroblasts which contribute to this process. Using a rabbit model, we have examined the effects of treating the synovial sheath with the antimetabolite 5-fluorouracil (5-FU) for five minutes. Inflammatory, proliferative and molecular markers were compared in the response of the treated and control tendons to injury. Compared with a control group we found that the proliferative and inflammatory responses were significantly reduced (p < 0.001) in the treated tendons. Not only was there a reduction in the cellular and cytokine response, but there also was a significant (p < 0.001) reduction in the level of activity of the known pro-scarring agent, transforming growth factor beta 1 (TGF-β1). These pilot studies indicate that the formation of restrictive adhesions may be modulated using a simple single-touch technique in the hope of producing a better return of function

A variety of scaffolds, including collagen-based membranes, fleeces and gels are seeded with osteoblasts and applied for the regeneration of bone defects. However, different materials yield different outcomes, despite the fact that they are generated from the same matrix protein, i.e. type I collagen. Recently we showed that in fibroblasts MMP-3 is induced upon attachment to matrix proteins in the presence of TGFbeta. Aim: To investigate the regulation of matrix metalloproteinases (MMPs) and interleukins (IL) in osteoblasts upon attachment to type I collagen (col-1) in comparison to laminin -1 (LM-111) in the presence or absence of costimulatory signals provided by transforming growth factor beta (TGFbeta). Methods: Osteoblasts were seeded in col-1–and LM-111-coated flasks and activated by the addition of TGFbeta. Mock-treated cells served as controls. The expression of genes was investigated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunocytochemistry and ELISA. Results: Attachment of osteoblasts to col-1 or LM-111 failed to activate the expression of MMPs or ILs. In contrast, TGFbeta induced the expression of MMP-3, MMP-9, and MMP-13, IL-6 and IL-16 mRNAs. MMP-3 was found to be elevated in supernatants of activated cells. No difference was found in the expression of MMP-1, IL-8 and IL–18. Interestingly, the expression of IL-1beta mRNA was not activated by TGFbeta alone, but it was activated by attachment of osteoblasts to LM-111 in the presence of TGFbeta. Conclusion: In contrast to fibroblasts, attachment of osteoblasts to col-1 or LM-111 had no effect on the induction of MMPs and ILs. TGFbeta induced the expression of MMPs and ILs in these cells but only MMP-3 was released. The results show significant differences between osteoblasts and fibroblasts in the effects of attachment to scaffold materials. This may have important consequences for tissue engineering of bone and for wound healing after surgery

Introduction: Abnormal fracture healing in aged, post-menopausal or ovariectomised patients remains a clinical problem. Understanding the distribution and regulation of biomolecular factors in fracture healing in oestrogen deficient rats may have clinical implications for developing novel therapeutic strategies for enhancing osteoporotic fracture healing. Our previous work demonstrated that bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-ß) and their signal transducers, Smads, played important roles in normal fracture healing. Insulin-like growth factor I (IGF-I) has been indicated playing a role in the maintenance of bone mass. Matrix metalloproteinases (MMPs) has been indicated to play a role in bone matrix degradation. Those factors in ovariectomised fracture healing have not yet been reported. Aim: To investigate the expression of BMP-2, 7, TGF-ß, Smads1–7, IGF-I, IGF-I receptor 1a (IGF-IR1), MMPs and TIMPs by a quantitative immunohistochemistry in a fracture model in an ovariectomised rodent (OVX). Methods: Age-matched, normal, female rats served as controls. The animals were sacrificed in groups of six at one, two, three, four and six weeks after the fracture. Results: The highlights of our results were the lack of IGF-I in the early stage of fracture healing (up to two weeks) in OVX rats and the greater expression of MMP-1 in OVX rats at all groups when compared with the normal rats. Conclusions: Our data suggested that the regulation downward of IGF-I in the OVX fractures resulted from estrogen deficiency and may have the function to stimulate MMP-1 activity. Over-expressed MMP-1 degraded collagen matrix in the cortex and inhibited the woven bone matrix formation during OVX fracture healing

Dupuytren’s contracture is characterised by abnormal fibroblast proliferation and extracellular matrix deposition in the palmar fascia. Fibroblast proliferation and matrix deposition in connective tissues are regulated by cytokines. A number of cytokines including transforming growth factor beta (TGFβ), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF) and epidermal growth factor (EGF) are known to have potent anabolic effects on connective tissue. The aim of this study was to investigate the role played by anabolic cytokines in the pathogenesis of Dupuytren’s disease. Twelve specimens of Dupuytren’s contracture and six control specimens of palmar fascia obtained from patients undergoing carpal tunnel release were cultured using a serumless method under standard conditions for 72 h. Levels of TGFβ-1, bFGF, PDGF and EGF in the medium were estimated using an enzyme linked immunoabsorbent assay technique. Neither Dupuytren’s tissue nor control palmar fascia produced any EGF. The mean (±S.D.)levels of bFGF, PDGF and TGFβ-1 produced by cultured palmar fascia were: 1270 ± 832, 74 ± 24, < 7, and for Dupuytren’s tissue were 722 ± 237, 139 ± 76.6, 645 ± 332, respectively. The levels of PDGF and TGFβ-1 were significantly higher in Dupuytren’s tissue. PDGF is produced in increased amounts by Dupuytren’s tissue. This may contribute to the fibroblast proliferation and increased ECM deposition observed in this condition. TGFβ-1 is not produced by normal palmar fascia but is produced in large amounts by Dupuytren’s tissue. The major physiologic role of TGFβ-1 is to stimulate formation of fibrous tissue. It plays a major role in wound healing and also in pathological conditions where fibrosis is a prominent feature. Inappropriate production of TGFβ-1 in the palmar fascia in Dupuytren’s disease may play a central role in initiating and stimulating the abnormal fibroblast proliferation and collagen synthesis seen in this condition

Bone morphogenic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) family and play a central role in bone formation. These morpho-gens are known to be present in bone matrix however the characteristics of their release during the grafting process has not previously been defined. The aim of this study was to determine the release BMP-7 (osteogenic protein; OP-1) from cancellous allograft that occurs during impaction grafting for revision hip arthroplasty. Forty, 10mm cubes of cancellous bone were accurately cut from the central region of 7 fresh frozen femoral heads. The cubes were centrifuged and washed to remove the marrow contents. The cubes were then individually washed and the fluid assayed for BMP-7 activity using a commercially available enzyme linked immuno-sorbent assay kit (Raybiotech Inc.). The cubes were then divided into 4 groups with samples from each femoral head in each group. Each group was subjected to strain of either 20%, 40%, 60% or 80% using a material testing machine. The cubes were then individually washed again and the wash fluid analysed for BMP-7 activity. BMP-7 activity was found to be present in all groups. Release of BMP-7 was found to increase with increasing strain. At 80% strain the mean concentration of BMP-7 released (830 pg/g) was 58% greater than that released at 60% strain (527 pg/g), 150% greater than the concentration at 40% strain (333 pg/g) and 476% greater than at 20% strain (144 pg/g). The differences between release at 80% and 40% strain and between 80% and 20% strain were statistically significant (p=0.036, p=0.002). Activity of BMP-7 in fresh frozen cancellous allograft bone has not previously been demonstrated. This study shows that the freezing and storage of femoral heads allows some maintenance of biological activity. Furthermore we have shown that BMP-7 may be released in proportion to the strain applied to the bone. This confirms that the process of impaction of bone morsels during revision hip arthroplasty may release BMPs that could aid in the incorporation and remodelling of the allograft

Bone morphogenetic proteins are low molecular weight proteins which have extensive similarity in structure and function to the transforming growth factor beta factors. They bind receptors on the surface of osteoprogenitor stem cells and activate intracellular signal transduction cascades resulting in the osteoblastic differentiation of pluripotential stem cells. Bone morphogenetic proteins (BMP) are being increasingly used in orthopaedic surgery including spinal fusion. These small molecules are capable of inducing bone formation when delivered in the appropriate concentration and on the appropriate scaffold. Recombinant BMP usually is combined with an osteoconductive carrier to form a composite graft. The osteoconductive carrier not only supports cellular adhesion but restricts the diffusion of these soluble factors away from the fusion site increasing local concentration of BMP. There is currently no consensus as to the ideal carrier but the optimal carrier may be dependent upon the specific clinical application for which it is used. In addition osteogenic cells that are able to respond to these osteoinductive signals must also be present for a successful spinal fusion to occur. Not all BMPs are equally effective. Over 15 BMPs have been identified and there are currently only two Food and Drug Administration (FDA)-approved BMPs (BMP-2 with a full PMA approval and BMP-7 with an HDE approval). Recombinant BMPs have been used successfully in anterior lumbar interbody fusions. Multiple animal studies have shown recombinant human BMP to be superior to autograft in the cervical, thoracic and lumbar spine, while human clinical trials have also shown recombinant human BMP-2 to be superior to autograft for anterior fusion. Similarly, multiple animal studies and clinical trials have shown that recombinant human BMPs result in equivalent or superior fusion rates for posterior spinal fusion compared to autograft. The use of BMPs may obviate the need for decortication and overcome the negative effects of nicotine and anti-inflammatories. In all studies, the concentration of BMPs necessary to produce successful spinal fusion was substantially greater than physiological levels, raising several potential safety concerns including bony overgrowth and bone formation which may lead to neural compression or unintended extension of the fusion. There are also the risks of local toxicity and a host immunologic response. These potential complications related to off-label use of BMPs need to be understood. For this reason, it is essential to determine the appropriate dose for each clinical application and develop efficient carrier systems. There are economic concerns associated with the use of this new technology. A single treatment of recombinant human BMP is expensive but may be cost effective if clinical outcomes are improved or other costs are avoided. The increased cost of BMP may offset the complications associated with harvesting autograft bone. When used properly, these molecules have the potential to eliminate the need for iliac crest bone graft harvest and improve the speed and success of spinal fusion

Growth factors hold great promise for the treatment of various musculoskeletal conditions. Growth factors are small proteins that serve as signaling agents for cells. The discovery of these substances revolutionized the field of cell biology by revealing the mechanism of regulation of cell activities. Growth factors are present in plasma or tissues at concentrations measured in billionths of a gram yet they are the principal effector of such critical cellular functions such as cell division, matrix synthesis and tissue differentiation. Several growth promoting substances have been identified in bone matrix and at the site of healing fractures. Among these are the transforming growth factor beta’s, bone morphogenetic proteins, fibroblast growth factors, insulin like growth factors and platelet derived growth factor. These growth factors are mainly produced by osteoblasts and incorporated into the extracellular matrix during bone formation. Small amounts of the growth factors can also be trapped systemically from serum and be incorporated into matrix. The present hypothesis is that growth factors are located within the matrix until remodeling or trauma causes solubilization and release of the proteins. The discovery of growth factors and their study in in vitro cultures has allowed an understanding of the mechanism of the regulation of a broad range of cell activities. However, their presence in plasma and tissues in minute quantities limited their evaluation in vivo and precluded clinical application of the natural purified products. Advances in recombinant DNA methodology have allowed sufficient quantities of these materials to be produced and many are in various stage of in vivo pre-clinical and clinical evaluation. Extensive efforts have been made to find methods by which growth factors can be used to stimulate local bone healing and bone formation in a variety of clinical models. The growth factors TGF-α, BMP and basic FGF are the only growth factors that have been demonstrated to possess substantial in vivo bone stimulatory capacity. The growth factors BMP-2 and BMP-7, also known as osteogenic protein-1, are in the final stages of pivotal human trials. There are many challenges to the clinical application of growth factors. It is unlikely that cell signaling molecules act independently of each other or are present in isolation from each other at their sites of action. The therapeutic application of growth factors must also accommodate the fact that most factors have a widespread and varied distribution of target cells. A growth factor administered to elicit a desired response from one cell type may also influence other cell types possible in unintended or undesirable ways. Finally, in the current era of cost consciousness in health care, a growth factor treatment must demonstrate cost effectiveness along with clinical efficacy

Arthrodesis of the spine is the preferred surgical treatment for a number of pathological disorders. This process is dependent on three primary components: osteogenic cells with osteoblastic potential, osteoinductive growth factors and an osteoconductive scaffold that facilitates bone formation and vascular ingrowth. Several systemic and local factors are known to affect the rate of spinal fusion. Autogenous bone graft remains the gold standard graft material for spinal fusion. It is the only graft material that supplies the three primary components necessary for a solid fusion. Unfortunately autogenous bone is only available in limited quantities and the procurement of autograft is associated with significant donor site morbidity. A number of different bone graft materials have been developed as alternatives to autograft. These materials may be classified into two major groups, bone graft extenders used to augment autograft, or bone graft substitutes. Several different bone graft materials have been developed including allograft, osteoconductive matrices, demineralised bone matrices, bone marrow aspiration, autologous platelet concentration, growth factors and gene therapy. Allograft is currently the most widely used substitute for autogenous bone. Because any osteogenic cells are eradicated during the tissue processes, allograft is primary osteoinductive with minimal osteoinductive potential. Processing may affects the structural and biological characteristics of a graft. The incorporation of allograft occurs by a process similar to that observed with autograft but more slowly and is less complete. Osteoconductive scaffolds do not contain any osteogenic cells or osteoinductive factors and are used as a composite graft as a carrier for either osteogenic cells or osteoinductive growth factors. They are biocompatible and do not illicit a response. There is also no inherent risk of infection and availability is unlimited. These materials are brittle with poor mechanical properties and need to be protected from excessive biomechanical forces until fully incorporated. A number of osteoconductive scaffolds have been developed including ceramics, calcium sulfate, mineralized collagen, bioactive glasses, and porous metals. Dematerialized bone matrices (DMPs) are osteoinductive with variable osteoconductive properties. DMPs consist of Type I collagen and non-collagenous proteins including multiple signaling proteins. The osteoinductive activity of DMPs is due to a small fraction of bone morphogenic proteins. There is significant variability in the osteoinductive potentials and clinical efficacy of DBMs. DBMs are most effective when combined with autograft or bone marrow aspirate. Bone marrow aspiration provides osteogenetic cells and osteoinductive growth factors but must be combined with an osteoconductive carrier to form a composite graft. It is associated with minimal morbidity compared to the use of autograft and is easily obtained. Unfractionated bone marrow contains only moderate osteogenic potential. Selective retention technology can increase the number of osteogenic cells then combined with an osteoconductive carrier such as a collagen sponge or DBM. Activated platelets release multiple factors that may enhance bone formation by promoting chemotaxis, cellular proliferation and differentiation of stem cells. Platelets do not release BMPs so this autologous platelet concentrate is not inductive. Concentrated platelet rich plasma gel is combined with an osteoconductive scaffold or osteogenic cells to form a composite graft for implantation. The capacity for fusion by this technique may be inferior to autologous graft. Bone morphogenetic proteins are low molecular weight proteins related to the transforming growth factor beta superfamily. They bind receptors on the surface of osteoprogenitor stem cells and activate intracellular signal transduction cascades resulting in the osteoblastic differentiation of pluripotential stem cells. Recombinant BMPs are typically combined with an osteoconductive carrier to form a composite graft. Recombinant BMPs have been used successfully in spinal fusions and may be superior to autograft. Gene therapy involves the transfer of specific DNA sequence into target cells that express the protein of interest. Gene therapy may provide a more potent osteoinductive signal than recombinant growth factors because the sustained local release of osteogentic proteins may be more physiologic than the administration of a single large dose of recombinant factors. There are potential safety concerns and economic issues. Autogenous bone remains the gold standard of graft material; however composite grafts consisting of multiple materials may prove to be efficacious for stimulating a spinal fusion

Aims

Dupuytren’s contracture is characterized by increased fibrosis of the palmar aponeurosis, with eventual replacement of the surrounding fatty tissue with palmar fascial fibromatosis. We hypothesized that adipocytokines produced by adipose tissue in contact with the palmar aponeurosis might promote fibrosis of the palmar aponeurosis.

Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes – the main cellular components in BMAC – interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes.

Cite this article: Bone Joint Res 2024;13(9):462–473.

Aims

Exosomes (exo) are involved in the progression of osteoarthritis (OA). This study aimed to investigate the function of dysfunctional chondrocyte-derived exo (DC-exo) on OA in rats and rat macrophages.

Cite this article: Bone Joint Res 2023;12(3):199–201.