Biomedical subjects

R Lane Smith

Publications and source records attributed to R Lane Smith.

At least 19 recordsLinked to original sources

PubMed2007

Kinetics of polymethylmethacrylate particle-induced inhibition of osteoprogenitor differentiation and proliferation.

Periprosthetic bone loss induced by implant wear debris may be a combined effect of osteolysis and reduced bone formation resulting from particle-induced suppression of osteoprogenitor differentiation. This study investigated the time-dependent effects of polymethylmethacrylate (PMMA) particles on the osteogenic capability of bone marrow osteoprogenitor cells during the early phase of differentiation. Murine bone marrow cells were challenged with PMMA particles (0.30% v/v) on the first day of growth in osteogenic medium. Particles were removed from culture after 1, 3, and 5 days, respectively, after which cell growth in osteogenic medium was continued until the 15th day. Bone marrow osteoprogenitor cells exposed to particles during the first 5 days of differentiation showed complete, irreversible inhibition of proliferation, alkaline phosphatase expression, and mineralization. Osteoprogenitors exposed to particles for more than 5 days showed the same degree of inhibition, while those exposed to particles for less than 5 days showed a diminished inhibitory response. Conditioned medium from particle-treated cells did not suppress osteogenic development, demonstrating that suppression of osteogenesis was not due to secreted inhibitory factors. This study has shown that the early phase of osteoprogenitor differentiation is a crucial time period during which exposure to PMMA particles causes irreversible inhibition of osteogenesis.

Animals↗

PubMed2006

Effects of orthopaedic wear particles on osteoprogenitor cells.

Wear particles from total joint arthroplasties are constantly being generated throughout the lifetime of an implant. Since mesenchymal stem cells and osteoprogenitors from the bone marrow are the precursors of osteoblasts, the reaction of these cells to orthopaedic wear particles is critical to both initial osseointegration of implants and ongoing regeneration of the periprosthetic bed. Particles less than 5 microm can undergo phagocytosis by mature osteoblasts, with potential adverse effects on cellular viability, proliferation and function. The specific effects are dependent on particle composition and dose. Metal and polymer particles in non-toxic doses stimulate pro-inflammatory factor release more than ceramic particles of a similar size. The released factors inhibit markers of bone formation and are capable of stimulating osteoclast-mediated bone resorption. Mesenchymal stem cells and osteoprogenitors are also profoundly affected by wear particles. Titanium and polymethylmethacrylate particles inhibit bone cell viability and proliferation, and downregulate markers of bone formation in a dose- and time-dependent manner. Future studies should delineate the molecular mechanisms by which particles adversely affect mesenchymal stems cells and the bone cell lineage and provide strategies to modulate these effects.

Animals↗

PubMed2006

Polymethylmethacrylate particles inhibit osteoblastic differentiation of bone marrow osteoprogenitor cells.

Aseptic implant loosening of total joint replacements often results from particle-mediated bone loss, which may be a combined effect of osteolysis and suppressed bone formation. Bone regeneration in the prosthetic bed depends on the activity of osteoblasts and their differentiation from osteoprogenitors in the bone marrow. This study investigated the effects of polymethylmethacrylate (PMMA) particles on the ability of bone marrow osteoprogenitors to differentiate into osteoblasts in vitro. Murine bone marrow cells challenged with PMMA particles on the first day of differentiation in osteogenic medium showed a dose-dependent decrease in osteoprogenitor proliferation, alkaline phosphatase expression, and mineralization. Undifferentiated bone marrow cells pretreated with PMMA particles in nonosteogenic medium for 5 days also showed a dose-dependent loss in osteogenic potential, which was sustained throughout subsequent growth in particle-free, osteogenic medium. Bone marrow cells challenged with PMMA particles after the fifth day of differentiation in osteogenic medium showed significant reductions in cellular proliferation, but not alkaline phosphatase expression and mineralization, indicating that bone marrow cells were most sensitive to particle treatment during the first 5 days of differentiation. This study demonstrated that PMMA particles inhibit osteoblastic differentiation of bone marrow osteoprogenitor cells, which may contribute to periprosthetic bone loss and implant failure.

Animals↗

PubMed2006

Effects of hydrostatic pressure and transforming growth factor-beta 3 on adult human mesenchymal stem cell chondrogenesis in vitro.

This study examined the effects of intermittent hydrostatic pressure (IHP) and transforming growth factor-beta 3 on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. Chondrogenic gene expression was determined by quantifying mRNA signal levels for SOX9, a transcription factor critical for cartilage development and the cartilage matrix proteins, aggrecan and type II collagen. Extracellular matrix production was determined by weight and histology. IHP was applied to hMSCs in pellet culture at a level of 10 MPa and a frequency of 1 Hz for 4 h per day for periods of 3, 7, and 14 days. hMSCs responded to addition of TGF-beta 3 (10 ng/mL) with a greater than 10-fold increase (p < 0.01) in mRNA levels for each, SOX9, type II collagen, and aggrecan during a 14-day culture period. Applying IHP in the presence of TGF-beta 3 further increased the mRNA levels for these proteins by 1.9-, 3.3-, and 1.6-fold, respectively, by day 14. Chondrogenic mRNA levels were increased with just exposure to IHP. Extracellular matrix deposition of type II collagen and aggrecan increased in the pellets as a function of treatment conditions and time of culture. This study demonstrated adjunctive effects of IHP on TGF-beta 3-induced chondrogenesis and suggests that mechanical loading can facilitate articular cartilage tissue engineering.

Adult↗

PubMed2006

Dose- and time-dependent effects of cyclic hydrostatic pressure on transforming growth factor-beta3-induced chondrogenesis by adult human mesenchymal stem cells in vitro.

This study examined effects of varying magnitudes of intermittent hydrostatic pressure (IHP) applied for different times on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. hMSCs were exposed to 0.1, 1, and 10 MPa of IHP at a frequency of 1 Hz for 4 h/day for 3, 7, and 14 days in the presence of transforming growth factor (TGF-beta3). Chondrogenesis was characterized by gene expression, macromolecule production, and extracellular matrix deposition. Exposure of hMSCs to 0.1 MPa of IHP increased SOX9 and aggrecan mRNA expression by 2.2- and 5.6-fold, respectively, whereas type II collagen mRNA expression responded maximally at 10 MPa. Production of sulfated glycosaminoglycan responded to IHP of 1 MPa and 10 MPa, whereas collagen levels increased only at 10 MPa. Morphologically, matrix condensation occurred with increased IHP, concomitant with collagen expression. This study demonstrated that different levels of IHP differentially modulate hMSC chondrogenesis in the presence of TGF-beta3. The data suggest that tissue engineering of articular cartilage through application or recruitment of hMSCs can be facilitated by mechanical stimulation.

Adult↗

PubMed2006

Gene regulation ex vivo within a wrap-around tendon.

This study tested the hypothesis that physiologic tendon loading modulates the fibrous connective tissue phenotype in undifferentiated skeletal cells. Type I collagen sponges containing human bone marrow stromal cells (MSCs) were implanted into the midsubstance of excised sheep patellar tendons. An ex vivo loading system was designed to cyclically stretch each tendon from 0 to 5% at 1.0 Hz. The MSC-sponge constructs were implanted into 2 tendon sites: the first site subjected to tension only and a second site located at an artificially created wrap-around region in which an additional compressive stress was generated transverse to the longitudinal axis of the tendon. The induced contact pressure at the wraparound site was 0.55 +/- 0.12 MPa, as quantified by pressure-sensitive film. An MSC-sponge construct was maintained free swelling in the same bath as an unloaded control. After 2 h of tendon stretching, the MSC-sponge constructs were harvested and real-time PCR was used to quantify Fos, Sox9, Cbfa1 (Runx2), and scleraxis mRNA expression as markers of skeletal differentiation. Two hours of mechanical loading distinctly altered MSC differentiation in the wrap-around region and the tensile-only region, as evidenced by differences in Fos and Sox9 mRNA expression. Expression of Fos mRNA was 13 and 52 times higher in the tensile-only and wrap-around regions, respectively, compared to the free-swelling controls. Expression of Sox9 mRNA was significantly higher (2.5-3 times) in MSCs from the wraparound region compared to those from the tensile-only region or in free-swelling controls. In contrast, expression levels for Cbfa1 did not differ among constructs. Scleraxis mRNA was not detected in any construct. This study demonstrates that the physiologic mechanical environment in the wrap-around regions of tendons provides stimuli for upregulating early response genes and transcription factors associated with chondrogenic differentiation. These differentiation responses begin within as little as 2 h after the onset of mechanical stimulation and may be the basis for the formation of fibrocartilage that is typically found in the wrap-around region of mature tendons in vivo.

Animals↗

PubMed2005

Temporal effects of a COX-2-selective NSAID on bone ingrowth.

The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.

Animals↗

PubMed2005

Interleukin-1 modulates periprosthetic tissue formation in an intramedullary model of particle-induced inflammation.

UNLABELLED: Interleukin-1 (IL-1) is a proinflammatory cytokine that has been implicated in wear-debris associated total joint replacement failure. We hypothesized that the absence of the IL-1 type-1 receptor would mitigate the inflammatory response to titanium particles and decrease periprosthetic inflammatory tissue in a murine intramedullary rod model. METHODS: An intramedullary rod with and without commercially pure titanium particles was placed in the femora of 24 wild type mice (WT) and 24 mice lacking a functional type-1 receptor to IL-1. Femora were analyzed histologically and by ELISA of organ culture explant supernatants. RESULTS: The presence of titanium particles in WT mice stimulated increased expression of interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1) relative to rod only controls. In contrast, IL-6 and MCP-1 expression were diminished in IL-1r1-KO mice exposed to titanium particles. Additionally, the formation of a periprosthetic fibro-inflammatory membrane in IL-1r1-KO mice was blunted at 2 weeks when compared to that in wild-type mice. Inflammatory changes and the quality of periprosthetic bone of IL-1r1-KO mice was similar to WT mice in response to titanium particles. CONCLUSIONS: These results implicate IL-1 as an important modulator in the local inflammatory response to intramedullary titanium particles. MCP-1 appears to be significantly modulated in IL-1r1-KO mice in response to titanium particles. This may be responsible, in part, for the diminished periprosthetic membrane observed in IL-1r1-KO mice at 2 weeks. Expansion of this murine model of intramedullary particle-induced inflammation to other gene targets may contribute to a more mechanistic understanding of wear-debris associated prosthesis failure.

Animals↗

PubMed2005

Pharmacologic modulation of periprosthetic osteolysis.

Wear and periprosthetic osteolysis of total joint replacements continue to be the most important problems in arthroplasty surgery. Despite the introduction of improved technologies including alternative bearing surfaces for TJRs, wear is inevitable because of relative movement at different interfaces and processes such as electrolysis and material degradation. Worn, clinically failing implants need to be followed closely and revised when appropriate. However, early wear and minor osteolysis do not result necessarily in progressive failure of the prosthesis. Indeed such cases may be followed up clinically and radiographically to establish the functional and biologic sequelae of wear and the timeline of these events. This scenario provides an opportunity to modulate the adverse biologic reaction associated with wear particles that includes chronic inflammation, the foreign body response, and periprosthetic bone destruction. Currently, immunological events associated with wear particles are becoming understood more clearly. Strategies to mitigate adverse processes associated with wear debris include local or systemic administration of immune modulators, signaling molecules, anti-inflammatory agents and growth factors, and altering osteoclast function. Ultimately, prevention of accelerated wear and periprosthetic osteolysis will be achieved with improved bearing surfaces and prosthetic designs.

Anti-Inflammatory Agents↗

PubMed2005

Microarray analysis of mechanical shear effects on flexor tendon cells.

BACKGROUND: Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon strength. The authors hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing. METHODS: To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis. RESULTS: Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, the authors also found up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with the authors' microarray data. CONCLUSIONS: The authors demonstrate an overall antifibrotic expression pattern in response to shear stress in tendon cells that may provide insight into the mechanisms by which early mobilization decreases adhesion formation without impaired tendon healing.

Animals↗

PubMed2005

UHMWPE wear debris upregulates mononuclear cell proinflammatory gene expression in a novel murine model of intramedullary particle disease.

BACKGROUND: We examined the effects of ultra-high molecular weight polyethylene (UHMWPE) particles on mononuclear cell proinflammatory gene expression in a novel murine model. We hypothesized that mononuclear cell gene transcription of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1) would be upregulated by the addition of polyethylene particles in this murine intramedullary rod model. MATERIAL AND METHODS: The model involved a stainless steel Kirschner wire inserted retrograde with a line-to-line fit in bilateral femora of C57bl/6 mice. Additionally, the right femora were injected with 3 x 10(9) UHMWPE particles. Mononuclear marrow cells were isolated by bone marrow aspiration and Ficoll-Paque centrifugation at 2, 4 and 10 weeks post-surgery. Total RNA was isolated and real-time RT-PCR was performed to quantify gene expression. Histological specimens of explanted femora were also analyzed to track the changes in periprosthetic tissue. RESULTS: UHMWPE particles stimulated gene transcription in mononuclear cells when examined at 2, 4 and 10 weeks post-surgery, compared to the rod-only group. Relative levels of IL-1beta and MCP-1 mRNA increased in a linear fashion over the 10-week time-course. IL-6 mRNA showed increased expression which peaked at 4 weeks. TNF-alpha mRNA expression was variable and reached a minimum at 4 weeks. The addition of UHMWPE particles stimulated ingress of macrophages and multinuclear cells of macrophage origin to the bone-implant interface. INTERPRETATION: In this model, a single bolus of UHMWPE particles had a long-term effect on gene transcription in mononuclear cells which perpetuated a chronic inflammatory state. This murine model of intramedullary particle-induced inflammation simulates periprosthetic events associated with implant wear in humans, and may contribute to a more mechanistic understanding of wear-debris associated prosthesis failure.

Animals↗

PubMed2004

Proinflammatory mediator expression in a novel murine model of titanium-particle-induced intramedullary inflammation.

Wear debris from total joint replacement prostheses is implicated in periprosthetic osteolysis and implant loosening. The pathophysiology of this biological process remains unclear. Animal models of particle-induced osteolysis have proven useful in the study of specific tissue responses to wear debris. However, existing in vivo murine models of particle-mediated inflammation do not permit analysis of cortical bone degradation. This study describes a murine model of particle disease using an intramedullary rod in the mouse femur to parallel the clinical situation. The model consists of placing a 10-mm-long Kirschner wire retrograde in both femurs of C57b1/6 male mice via a medial parapatellar arthrotomy. Phagocytosable titanium particles were also implanted unilaterally to replicate generation of wear debris. Mice were sacrificed at 2, 10, and 26 weeks and whole femurs were cultured for 72 h. Levels of interleukin-6, monocyte chemotactic protein-1, and macrophage colony stimulating factor were assayed by ELISA. Transverse histological sections, at the level of the implant, were taken and stained with hematoxylin and eosin (H&E). Results demonstrated increased expression of proinflammatory mediators at 2 weeks in femora with rod and particles compared to femora with rods alone. Destruction of the endosteum was evident at 2, 10, and 26 weeks in the femora with titanium. This novel murine model of particle-induced intramedullary inflammation may facilitate cost-effective genetic studies and offers investigators a simple, clinically relevant intramedullary model to readily examine the pathogenesis of particle-mediated periprosthetic osteolysis.

Animals↗

PubMed2004

Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-alpha.

Although interleukin-1 (IL-1) has been implicated in the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are largely unknown. Recently, a cytokine-driven, stromal cell-free mouse osteoclastogenesis model was established. A combination of macrophage colony stimulating factor (M-CSF) and receptor activator of NFkappaB ligand (RANKL) was proven to be sufficient in inducing differentiation of bone marrow hematopoietic precursor cells to bone-resorbing osteoclasts in the absence of stromal cells or osteoblasts. This study utilizes this model to examine the impact of human IL-1beta on in vitro osteoclastogenesis of bone marrow progenitor cells. We found that osteoclast precursor cells failed to undergo osteoclastogenesis when treated with IL-1 alone. In contrast, IL-1 dramatically up-regulated osteoclastogenesis by 2.5- to 4-folds in the presence of RANKL and M-CSF. The effect can be significantly blocked by IL-1 receptor antagonist (p < 0.01). Tumor necrosis factor-alpha (TNF-alpha) was undetectable in the culture medium of differentiating osteoclasts induced by IL-1. Adding exogenous TNF-alpha neutralizing antibody had no influence on the IL-1-induced effect as well. These results show that in the absence of stromal cells, IL-1 exacerbates osteoclastogenesis by cooperating with RANKL and M-CSF, while TNF-alpha is not involved in this IL-1-stimulated osteoclast differentiation pathway.

Animals↗

PubMed2004

Effects of interleukin-10 on titanium particle-induced macrophage transcription factor activation and cytokine expression in vitro.

This study tests the hypothesis that transcription factor activation by exposure of macrophages to titanium particles can be modulated by the addition of the antiinflammatory cytokine, interleukin 10 (IL-10). The experiments were carried out with primary human monocyte/macrophages that were treated in the presence or absence of IL-10 with and without exposure to titanium particles. The time course for experiments varied from 1 h-5 h for analysis of nuclear protein and up to 48 h for analysis of cytokine release. Transcription factor translocation to the nucleus was analyzed using electrophoretic gel shift assays and cytokine release was quantified by enzyme-linked immunosorbent assay. Addition of titanium particles increased release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta). In addition, titantium particle induced translocation of the transcription factors, NF-kappa B and NF-IL6, in the nucleus within 1 h. Treatment of macrophages with IL-10 prior to exposure to titanium particles decreased translocation of NF-IL6 but did not significantly alter nuclear levels of NF-kappa B. In addition, pretreatment of the cells with IL-10 decreased particle-induced cytokine release. These data show that antiinflammatory cytokines may provide a mechanism by which particle-induced inflammatory response may be modulated in vivo.

CCAAT-Enhancer-Binding Protein-beta↗

PubMed2004

Intermittent hydrostatic pressure inhibits matrix metalloproteinase and pro-inflammatory mediator release from human osteoarthritic chondrocytes in vitro.

OBJECTIVE: This study tested the hypothesis that intermittent hydrostatic pressure applied to human osteoarthritic chondrocytes modulates matrix metalloproteinase and pro-inflammatory mediator release in vitro. DESIGN: Human osteoarthritic articular chondrocytes were isolated and cultured as primary high-density monolayers. For testing, chondrocyte cultures were transferred to serum-free medium and maintained without loading or with exposure to intermittent hydrostatic pressure (IHP) at 10 MPa at a frequency of 1 Hz for periods of 6, 12 and 24 h. Levels of matrix metalloproteinase-2, -9 (MMP-2, -9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and the pro-inflammatory mediators, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), released into the culture medium were assessed by ELISA. Matrix metalloproteinase activity was confirmed by zymographic analysis. RESULTS: In the absence of IHP, levels of MMP-2, TIMP-1, IL-6, and MCP-1 in the chondrocyte culture medium increased in a time-dependent manner. Application of IHP decreased MMP-2 levels at all time periods tested, relative to unloaded control cultures maintained for the same time periods. Although 84/82 kDa bands were faintly detectable by zymography, MMP-9 levels were not quantifiable in medium from loaded or unloaded cultures by ELISA. TIMP-1 levels were not altered in response to IHP at any time period tested. IL-6 and MCP-1 levels decreased in cultures exposed to IHP at 12 and 24 h, relative to unloaded control cultures maintained for the same time periods. CONCLUSION: IHP decreased release of MMP-2, IL-6 and MCP-1 by osteoarthritic chondrocytes in vitro suggesting that pressure influences cartilage stability by modulating chondrocyte expression of these degradative and pro-inflammatory proteins in vivo.

Cartilage, Articular↗

PubMed2004

A framework for the in vivo pathomechanics of osteoarthritis at the knee.

The in vivo pathomechanics of osteoarthritis (OA) at the knee is described in a framework that is based on an analysis of studies describing assays of biomarkers, cartilage morphology, and human function (gait analysis). The framework is divided into an Initiation Phase and a Progression Phase. The Initiation Phase is associated with kinematic changes that shift load bearing to infrequently loaded regions of the cartilage that cannot accommodate the loads. The Progression Phase is defined following cartilage breakdown. During the Progression Phase, the disease progresses more rapidly with increased load. While this framework was developed from an analysis of in vivo pathomechanics, it also explains how the convergence of biological, morphological, and neuromuscular changes to the musculoskeletal system during aging or during menopause lead to the increased rate of idiopathic OA with aging. Understanding the in vivo response of articular cartilage to its physical environment requires an integrated view of the problem that considers functional, anatomical, and biological interactions. The integrated in vivo framework presented here will be helpful for the interpretation of laboratory experiments as well as for the development of new methods for the evaluation of OA at the knee.

Aging↗

PubMed2004

The mechanobiology of articular cartilage development and degeneration.

The development, maintenance, and destruction of cartilage are regulated by mechanical factors throughout life. Mechanical cues in the cartilage fetal endoskeleton influence the expression of genes that guide the processes of growth, vascular invasion, and ossification. Intermittent fluid pressure maintains the cartilage phenotype whereas mild tension (or shear) promotes growth and ossification. The articular cartilage thickness is determined by the position at which the subchondral growth front stabilizes. In mature joints, cartilage is thickest and healthiest where the contact pressure and cartilage fluid pressure are greatest. The depth-dependent histomorphology reflects the local fluid pressure, tensile strain, and fluid exudation. Osteoarthritis represents the final demise and loss of cartilage in the skeletal elements. The initiation and progression of osteoarthritis can follow many pathways and can be promoted by mechanical factors including: (1) reduced loading, which activates the subchondral growth front by reducing fluid pressure; (2) blunt impact, causing microdamage and activation of the subchondral growth front by local shear stress; (3) mechanical abnormalities that increase wear at the articulating surface; and (4) other mechanically related factors. Research should be directed at integrating our mechanical understanding of osteoarthritis pathogenesis and progression within the framework of cellular and molecular events throughout ontogeny.

Animals↗

PubMed2004

Osteoarthritis: current treatment and future prospects for surgical, medical, and biologic intervention.

The treatment of osteoarthritis includes a wide spectrum of approaches. This article reviews current practices in medical, pharmaceutical and surgical treatment with a perspective toward the immediate, distant and far distant future. At present, with the exception of surgery, all other treatments are palliative. That is to say that many of these treatments relieve pain and increase function. However, on the basis of medical evidence, these treatments do not change the course of the disease. Surgical interventions, including joint replacement and osteotomy, reverse the progress of osteoarthritis and provide long-term improved function and pain relief for specific joints. The goal of treating osteoarthritis is to arrest and reverse its progress regionally or globally through biologic methodology. Meaningful progress for biologic intervention accumulates annually. Pluripotent mesenchymal cells can be coaxed into chondrocytes or stem cells. Cytokines, growth factors, chemokines, protease inhibitors, kinases, apoptosis, mechanics, and genetics are increasingly recognized to play key roles in the control of the articular cartilage behavior. Knowledge of their roles and relationships advance toward solutions related to osteoarthritis. In the future, biologic control may be harnessed to regrow joints or limbs, as currently occurs naturally in newts and salamanders. Fortunately, until then we have ever improving joint replacement.

Animals↗