Subarticular Spongiosa Research Articles

Locally Directed Recombinant Adeno- Associated Virus–Mediated IGF-1 Gene Therapy Enhances Osteochondral Repair and Counteracts Early Osteoarthritis In Vivo

Background: Restoration of osteochondral defects is critical, because osteoarthritis (OA) can arise. Hypothesis: Overexpression of insulin-like growth factor 1 (IGF-1) via recombinant adeno-associated viral (rAAV) vectors (rAAV-IGF-1) would improve osteochondral repair and reduce parameters of early perifocal OA in sheep after 6 months in vivo. Study Design: Controlled laboratory study. Methods: Osteochondral defects were created in the femoral trochlea of adult sheep and treated with rAAV-IGF-1 or rAAV-lacZ (control) (24 defects in 6 knees per group). After 6 months in vivo, osteochondral repair and perifocal OA were assessed by well-established macroscopic, histological, and immunohistochemical scoring systems as well as biochemical and micro–computed tomography evaluations. Results: Application of rAAV-IGF-1 led to prolonged (6 months) IGF-1 overexpression without adverse effects, maintaining a significantly superior overall cartilage repair, together with significantly improved defect filling, extracellular matrix staining, cellular morphology, and surface architecture compared with rAAV-lacZ. Expression of type II collagen significantly increased and that of type I collagen significantly decreased. Subchondral bone repair and tidemark formation were significantly improved, and subchondral bone plate thickness and subarticular spongiosa mineral density returned to normal. The OA parameters of perifocal structure, cell cloning, and matrix staining were significantly better preserved upon rAAV-IGF-1 compared with rAAV-lacZ. Novel mechanistic associations between parameters of osteochondral repair and OA were identified. Conclusion: Local rAAV-mediated IGF-1 overexpression enhanced osteochondral repair and ameliorated parameters of perifocal early OA. Clinical Relevance: IGF-1 gene therapy may be beneficial in repair of focal osteochondral defects and prevention of perifocal OA.

Modulation of early osteoarthritis by tibiofemoral re-alignment in sheep

ObjectiveTo investigate whether tibiofemoral alignment influences early knee osteoarthritis (OA). We hypothesized that varus overload exacerbates early degenerative osteochondral changes, and that valgus underload diminishes early OA. MethodNormal, over- and underload were induced by altering alignment via high tibial osteotomy in adult sheep (n = 8 each). Simultaneously, OA was induced by partial medial anterior meniscectomy. At 6 weeks postoperatively, OA was examined in five individual subregions of the medial tibial plateau using Kellgren-Lawrence grading, quantification of macroscopic OA, semiquantitative histopathological OA and immunohistochemical type-II collagen, ADAMTS-5, and MMP-13 scoring, biochemical determination of DNA and proteoglycan contents, and micro-computed tomographic evaluation of the subchondral bone. ResultsMultivariate analyses revealed that OA cartilaginous changes had a temporal priority over subchondral bone changes. Underload inhibited early cartilage degeneration in a characteristic topographic pattern (P ≥ 0.0983 vs. normal), in particular below the meniscal damage, avoided alterations of the subarticular spongiosa (P ≥ 0.162 vs. normal), and prevented the disturbance of otherwise normal osteochondral correlations. Overload induced early alterations of the subchondral bone plate microstructure towards osteopenia, including significantly decreased percent bone volume and increased bone surface–to–volume ratio (all P ≤ 0.0359 vs. normal). ConclusionThe data provide high-resolution evidence that tibiofemoral alignment modulates early OA induced by a medial meniscus injury in adult sheep. Since underload inhibits early OA, these data also support the clinical value of strategies to reduce the load in an affected knee compartment to possibly decelerate structural OA progression.

Osteochondral junction leakage and cartilage joint lubrication

Background and ObjectivesPrevious studies have shown that there is potentially interstitial fluid exchange between cartilage tissue and the subarticular spongiosa region in the case of injury or disease (e.g., osteoarthritis and osteoporosis). Interstitial flow is also required for cartilage lubrication under joint load. A key question then is how cartilage lubrication is modified by increased interstitial fluid leakage across the osteochondral junction. Thus, the purpose of this study is to develop a numerical model to investigate changes in cartilage lubrication with changes in osteochondral junction leakage. MethodsThe multi-phase coupled model includes domains corresponding to the contact gap, cartilage tissue and subchondral bone plate region (ScBP). Each of these domains are treated as poroelastic systems, with their coupling implemented through mass and pressure continuity. The effects of osteochondral junction leakage on lubrication were investigated with a parametric study on the relative permeability between the ScBP and cartilage tissue. ResultsSignificant effects of ScBP permeability were predicted, especially during the early stage of the junction leakage development (early stage of the disease). There is a significant reduction in mixed-mode lubrication duration under the effect of increased junction leakage (the cartilage tissue mixed-mode lubrication duration is about 33% decrease for a relative permeability ratio of 0.1 between ScBP and cartilage tissue, and about 52% decrease under the osteoarthritis condition). In addition, the time for cartilage to reach steady-state consolidation is significantly reduced when ScBP permeability increases (the consolidation time reduces from roughly 2 h to 1.2 h when the relative permeability ratio increases from 0.001 to 0.1, and it reduces to 0.8 h for an advanced osteoarthritis condition). It is predicted that the initial friction coefficient could increase by over 60% when the ScBP permeability is consistent with an advanced osteoarthritis (OA) condition. ConclusionIncreased osteochondral junction leakage induced by joint injury and disease could result in increased cartilage surface wear rates due to more rapid interstitial fluid depressurization within articular cartilage.

Subchondral Drilling Independent of Drill Hole Number Improves Articular Cartilage Repair and Reduces Subchondral Bone Alterations Compared With Debridement in Adult Sheep

Background: Subchondral drilling is an established marrow stimulation technique for small cartilage defects, but whether drilling is required at all and if the drill hole density affects repair remains unclear. Hypotheses: Osteochondral repair is improved when the subchondral bone is perforated by a higher number of drill holes per unit area, and drilling is superior to defect debridement alone. Study Design: Controlled laboratory study. Methods: Rectangular full-thickness chondral defects (4 × 8 mm) were created in the trochlea of adult sheep (N = 16), debrided down to the subchondral bone plate without further treatment as controls (no treatment; n = 7) or treated with either 2 or 6 (n = 7 each) subchondral drill holes (diameter, 1.0 mm; depth, 10.0 mm). Osteochondral repair was assessed at 6 months postoperatively by standardized (semi-)quantitative macroscopic, histological, immunohistochemical, biochemical, and micro–computed tomography analyses. Results: Compared with defect debridement alone, histological overall cartilaginous repair tissue quality (P = .025) and the macroscopic aspect of the adjacent cartilage (P≤ .032) were improved after both drilling densities. Only drilling with 6 holes increased type 2 collagen content in the repair tissue compared with controls (P = .038). After debridement, bone mineral density was significantly decreased in the subchondral bone plate (P≤ .015) and the subarticular spongiosa (P≤ .041) compared with both drilling groups. Debridement also significantly increased intralesional osteophyte sectional area compared with drilling (P≤ .034). No other differences in osteochondral repair existed between subchondral drilling with 6 or 2 drill holes. Conclusion: Subchondral drilling independent of drill hole density significantly improves structural cartilage repair compared with sole defect debridement of full-thickness cartilage defects in sheep after 6 months. Subchondral drilling also leads to a better reconstitution of the subchondral bone compartment below the defects. Simultaneously, drilling reduced the formation of intralesional osteophytes caused by osseous overgrowth compared with debridement. Clinical Relevance: These results have important clinical implications, as they support subchondral drilling independent of drill hole number but discourage debridement alone for the treatment of small cartilage defects. Clinical studies are warranted to further quantify the effects of subchondral drilling in similar settings.

Distributional patterns of subchondral bone density and histopathological features of the first tarsometatarsal joint in hallux valgus feet

BackgroundHypermobility of the first tarsometatarsal (TMT) joint is frequently identified in patients with hallux valgus (HV); however, its association with the development of osteoarthritis in the first TMT joint in such patients remains unknown. The purpose of this study was to clarify the distribution of subchondral bone density of the first TMT joint via computed tomography (CT) using Hounsfield units (HU).MethodsPatients were divided into three groups: the osteotomy (20 feet; 20 women, mean age: 61.8 years), arthrodesis (23 feet; two men, 21 women, 71.2 years), and control group (patients without HV deformity who had undergone CT scans of the foot; 13 feet; seven men, six women, 29.7 years). The HU ratios were calculated, which were defined as the HU value of each subdivision of the subarticular spongiosa of the first TMT joint [dorsomedial (DM), dorsolateral (DL), plantomedial (PM), and plantolateral (PL)] divided by the HU values of the entire joint surface. The ratios for the osteotomy, arthrodesis, and control groups were compared. The degradation of the articular cartilage in the first TMT joint was histologically graded in the arthrodesis group. Tukey–Kramer multiple comparison analysis was conducted to compare the HU ratios among the three groups, and the histological grade in each subdivision.ResultsThe arthrodesis group demonstrated high HU ratios in the DM area of the medial cuneiform, and significantly lower HU ratios in the PL area of the first metatarsal. Lower HU ratios in the DL area were observed in both the osteotomy and the arthrodesis group when compared to that in the medial cuneiform of the control group. The histological evaluation indicated nearly normal articular cartilage for all subdivided areas in both the medial cuneiform and the first metatarsal in patients with severe HV.ConclusionsAlthough high subchondral bone density was identified in the DM area of the medial cuneiform in severe HV, only mild degradation was histologically observed in the articular cartilage of the first TMT joint. Our findings suggest that the indications for arthrodesis of the first TMT should be reconsidered based on the severity of the degenerative changes in the first TMT joint.

Role of the Subchondral Bone in Articular Cartilage Degeneration and Repair.

The subchondral bone has long been recognized as playing an important role in articular cartilage repair.1 From an anatomic standpoint, the subchondral bone is the bony lamella that lies below the calcified zone of the articular cartilage, separated by the cement line. Trabeculae arising from the subchondral bone plate form a spongious network, the subarticular spongiosa. The term osteochondral unit reflects the close interaction between these two tissues of dissimilar intrinsic repair capacities. Here, we focus on novel translational data on the role of the subchondral bone in the development of osteoarthritis (OA) and in the field of reconstructive therapies for focal articular cartilage defects. Role of Subchondral Bone in Early Osteoarthritis OA is considered a disease of the entire joint, with biochemical and molecular crosstalk and signaling pathways between all affected tissues (ie, cartilage, bone, synovium, meniscus, capsule, ligaments, muscles), leading to abnormal joint remodeling by failure of the natural repair processes.2,3 Subchondral bone plays an important role early in the development of OA.1 In early OA, thickness of both the subchondral bone plate and subarticular spongiosa is increased,4 mineral content is reduced, and trabecular integrity is altered.5 Intriguingly, such a pattern co-localizes with regions of articular cartilage damage.6,7 Although the final primacy of these alterations remains to be determined, recent data show that when defined subchondral bone changes are established, articular cartilage damage may be induced.8 Systemic administration of PTH 1-34, the 1-34 amino acid segment of parathyroid hormone, induced an enhanced volume, mineral density, and microarchitecture of the subarticular spongiosa, together with a broadened calcified cartilage layer, in a previously normal osteochondral unit in vivo. Such alterations of calcified tissues may therefore lead to an instigation of early degeneration of the hyaline cartilage.8,9 These findings support the paradigm of a close crosstalk within the osteochondral unit under physiologic and pathologic conditions.3 Relevance of Subchondral Bone for Reconstructive Cartilage Repair Several pathologic features of subchondral bone emerge in a temporally precise fashion during spontaneous and therapeutic repair of chondral and osteochondral defects. These features include structural alterations of the subchondral bone microstructure, the advancement of the subchondral bone plate toward the joint line, the formation of intralesional osteophytes, and the appearance of subchondral bone cysts. Possible causes include, but may not be limited to, impaired osteochondral crosstalk and regeneration, pathologic consequences of altered biomechanical loading, and pathologic vascularization or angiogenesis.10 Many translational studies showed a lack of correlation between cartilage and subchondral bone repair, suggesting that independent repair pathways take place within these tissues.10 In animal models, the subchondral bone plate advancement arises earlier in small animals but is more pronounced in the long term in large animal models. Clinical investigations have also demonstrated subchondral bone changes after cartilage repair. Although initially ascribed to marrow-stimulation techniques, such changes were also observed in the context of autologous chondrocyte implantation. These observations suggest that none of these different approaches for cartilage repair is superior with regard to subchondral bone pathologies.11 Recently, strategies to diminish subchondral bone alterations were developed. Marrow stimulation is still the most commonly used cartilage repair procedure, but there is little consensus on basic technical parameters. Mechanistically, the procedure induces multiple standardized small bone injuries in the subchondral bone plate. Current data from translational models of marrow stimulation support the value of small-diameter instruments, in contrast to instruments with larger diameters.12 For example, small subchondral drill holes that reflect the physiologic subchondral trabecular distance improve osteochondral repair more effectively than do larger drill holes.13 Likewise, small-diameter microfracture awls improved articular cartilage repair in a translational sheep model more effectively than did larger awls.14 These data suggest that smaller subchondral bone perforations allow for a better reconstitution of the microarchitecture of the subchondral bone plate and subarticular spongiosa, although the dimension of the opening of the subchondral bone plate also proportionally affects the number of possible recruited mesenchymal stem cells (which, in theory, may accelerate cartilage repair). Altogether, these data support the use of small instruments for the surgical treatment of cartilage defects and have important clinical implications in the execution of marrow stimulation. Summary In light of recent studies, subchondral bone continues to provide important information about the development of OA. Results from several translational models demonstrate the critical importance of the structural integrity of subchondral bone because its protection improves reconstructive therapies for focal cartilage defects. Given the still incomplete understanding about the mechanisms of OA and cartilage repair, enhanced knowledge of the basic science and clinical events in this frontier region will likely translate into improved therapeutic strategies for osteochondral regeneration.

Small-Diameter Awls Improve Articular Cartilage Repair After Microfracture Treatment in a Translational Animal Model

Background: Microfracture is the most commonly applied arthroscopic marrow stimulation procedure. Hypothesis: Articular cartilage repair is improved when the subchondral bone is perforated by small-diameter microfracture awls compared with larger awls. Study Design: Controlled laboratory study. Methods: Standardized rectangular (4 × 8 mm) full-thickness chondral defects (N = 24) were created in the medial femoral condyle of 16 adult sheep and debrided down to the subchondral bone plate. Three treatment groups (n = 8 defects each) were tested: 6 microfracture perforations using small-diameter awls (1.0 mm; group 1), large-diameter awls (1.2 mm; group 2), or without perforations (debridement control; group 3). Osteochondral repair was assessed at 6 months in vivo using established macroscopic, histological, immunohistochemical, biochemical, and micro–computed tomography analyses. Results: Compared with control defects, histological cartilage repair was always improved after both microfracture techniques (P < .023). Application of 1.0-mm microfracture awls led to a significantly improved histological overall repair tissue quality (7.02 ± 0.70 vs 9.03 ± 0.69; P = .008) and surface grading (1.05 ± 0.28 vs 2.10 ± 0.19; P = .001) compared with larger awls. The small-diameter awl decreased relative bone volume of the subarticular spongiosa (bone volume/tissue volume ratio: 23.81% ± 3.37% vs 30.58% ± 2.46%; P = .011). Subchondral bone cysts and intralesional osteophytes were frequently observed after either microfracture treatment. Macroscopic grading, DNA, proteoglycan, and type I and type II collagen contents as well as degenerative changes within the adjacent cartilage remained unaffected by the awl diameter. Conclusion: Small-diameter microfracture awls improve articular cartilage repair in the translational sheep model more effectively than do larger awls. Clinical Relevance: These data support the use of small microfracture instruments for the surgical treatment of cartilage defects and warrant prolonged clinical investigations.

High resolution MRI imaging at 9.4 Tesla of the osteochondral unit in a translational model of articular cartilage repair.

BackgroundNon-destructive structural evaluation of the osteochondral unit is challenging. Here, the capability of high-field magnetic resonance imaging (μMRI) at 9.4 Tesla (T) was explored to examine osteochondral repair ex vivo in a preclinical large animal model. A specific aim of this study was to detect recently described alterations of the subchondral bone associated with cartilage repair.MethodsOsteochondral samples of medial femoral condyles from adult ewes containing full-thickness articular cartilage defects treated with marrow stimulation were obtained after 6 month in vivo and scanned in a 9.4 T μMRI. Ex vivo imaging of small osteochondral samples (typical volume: 1–2 cm3) at μMRI was optimised by variation of repetition time (TR), time echo (TE), flip angle (FA), spatial resolution and number of excitations (NEX) from standard MultiSliceMultiEcho (MSME) and three-dimensional (3D) spoiled GradientEcho (SGE) sequences.ResultsA 3D SGE sequence with the parameters: TR = 10 ms, TE = 3 ms, FA = 10 °, voxel size = 120 × 120 × 120 μm3 and NEX = 10 resulted in the best fitting for sample size, image quality, scanning time and artifacts. An isovolumetric voxel shape allowed for multiplanar reconstructions. Within the osteochondral unit articular cartilage, cartilaginous repair tissue and bone marrow could clearly be distinguished from the subchondral bone plate and subarticular spongiosa. Specific alterations of the osteochondral unit associated with cartilage repair such as persistent drill holes, subchondral bone cysts, sclerosis of the subchondral bone plate and of the subarticular spongiosa and intralesional osteophytes were precisely detected.ConclusionsHigh resolution, non-destructive ex vivo analysis of the entire osteochondral unit in a preclinical large animal model that is sufficient for further analyses is possible using μMRI at 9.4 T. In particular, 9.4 T is capable of accurately depicting alterations of the subchondral bone that are associated with osteochondral repair.

Structural changes in the lateral tibiofemoral compartment after high tibial osteotomy

Valgus high tibial osteotomy (HTO) increases the pressure in the lateral tibiofemoral compartment. The purpose of this work is to provide an overview about current knowledge on the effect of HTO on the lateral tibiofemoral osteochondral unit and lateral meniscus. Studies in translational models on the effect of medial opening wedge HTO on the lateral tibiofemoral osteochondral unit and lateral meniscus are reviewed and placed in the clinical perspective. Emphasis is placed on specific correlations between topographical alterations of the cartilage, subchondral bone, and meniscus in the lateral tibiofemoral compartment. Specific topographical relationships exist in the central region between the articular cartilage and subchondral bone plate thickness, and in the submeniscal periphery between the articular cartilage and lateral meniscus, emphasizing the important protective role of the lateral meniscus. Following standard correction, the pressure increase in the lateral compartment following valgus HTO does not induce significant structural changes in the lateral tibiofemoral compartment. A higher increase in pressure following valgus overcorrection induces adaptive changes in the lateral compartment, reflected by an increased specific bone surface (BS/BV) in the subarticular spongiosa compared with unloading by varisation. Valgus overcorrection also leads to a decrease in the number of cells in the red-red (peripheral) zone of the middle third of the lateral menisci, without structural changes. In conjunction with the clinical data these results show that opening wedge HTO is a safe procedure for the lateral tibial osteochondral unit and the lateral meniscus.

Small Subchondral Drill Holes Improve Marrow Stimulation of Articular Cartilage Defects

Background: Subchondral drilling is an established marrow stimulation technique. Hypothesis: Osteochondral repair is improved when the subchondral bone is perforated with small drill holes, reflecting the physiological subchondral trabecular distance. Study Design: Controlled laboratory study. Methods: A rectangular full-thickness chondral defect was created in the trochlea of adult sheep (n = 13) and treated with 6 subchondral drillings of either 1.0 mm (reflective of the trabecular distance) or 1.8 mm in diameter. Osteochondral repair was assessed after 6 months in vivo by macroscopic, histological, and immunohistochemical analyses and by micro–computed tomography. Results: The application of 1.0-mm subchondral drill holes led to significantly improved histological matrix staining, cellular morphological characteristics, subchondral bone reconstitution, and average total histological score as well as significantly higher immunoreactivity to type II collagen and reduced immunoreactivity to type I collagen in the repair tissue compared with 1.8-mm drill holes. Analysis of osteoarthritic changes in the cartilage adjacent to the defects revealed no significant differences between treatment groups. Restoration of the microstructure of the subchondral bone plate below the chondral defects was significantly improved after 1.0-mm compared to 1.8-mm drilling, as shown by higher bone volume and reduced thickening of the subchondral bone plate. Likewise, the microarchitecture of the drilled subarticular spongiosa was better restored after 1.0-mm drilling, indicated by significantly higher bone volume and more and thinner trabeculae. Moreover, the bone mineral density of the subchondral bone in 1.0-mm drill holes was similar to the adjacent subchondral bone, whereas it was significantly reduced in 1.8-mm drill holes. No significant correlations existed between cartilage and subchondral bone repair. Conclusion: Small subchondral drill holes that reflect the physiological trabecular distance improve osteochondral repair in a translational model more effectively than larger drill holes. Clinical Relevance: These results have important implications for the use of subchondral drilling for marrow stimulation, as they support the use of small-diameter bone-cutting devices.

Effect of open wedge high tibial osteotomy on the lateral tibiofemoral compartment in sheep. Part III: analysis of the microstructure of the subchondral bone and correlations with the articular cartilage and meniscus.

First, to evaluate whether medial open wedge high tibial osteotomy (HTO) induces alterations of the microstructure of the lateral tibial subchondral bone plate of sheep. Second, to test the hypothesis that specific correlations exist between topographical structural alterations of the subchondral bone, the cartilage and the lateral meniscus. Three experimental groups received biplanar osteotomies of the right proximal tibiae: (a) closing wedge HTO (4.5° of tibial varus), (b) opening wedge HTO (4.5° tibial valgus; standard correction) and (c) opening wedge HTO (9.5° of valgus; overcorrection), each of which was compared to the non-osteotomised contralateral proximal tibiae. After 6months, subchondral bone structure indices were measured by computed tomography. Correlations between the subchondral bone, the articular cartilage and the lateral meniscus were determined. Increased loading by valgus overcorrection led to an enlarged specific bone surface (BS/BV) in the subarticular spongiosa compared with unloading by varisation. The subchondral bone plate was 3.9-fold thicker in the central region of the lateral tibial plateau than in the submeniscal periphery. Its thickness in the central region significantly correlated with the thickness of the articular cartilage. In the submeniscal region, such correlation did not exist. In general, a higher degree of osteoarthritis (OA) correlated with alterations of the subchondral bone plate microstructure. OA of the submeniscal articular cartilage also correlated with worse matrix staining of the lateral meniscus. Osteoarthritis changes are associated with alterations of the subchondral bone plate microstructure. Specific topographical relationships exist in the central region between the articular cartilage and subchondral bone plate thickness, and in the submeniscal periphery between and the articular cartilage and lateral meniscus. From a clinical perspective, the combined follow-up data from this and the previous two investigations suggest that open wedge valgus HTO is a safe procedure for the lateral compartment to manage medial osteoarthritis of the knee with varus malalignment in the short term.

PTH [1-34]-induced alterations of the subchondral bone provoke early osteoarthritis

To test the hypothesis that changes in the subchondral bone induced by parathyroid hormone (PTH [1-34]) reciprocally affect the integrity of the articular cartilage within a naïve osteochondral unit invivo. Daily subcutaneous injections of 10μg PTH [1-34]/kg were given to adult rabbits for 6 weeks, controls received saline. Blood samples were continuously collected to monitor renal function. The subchondral bone plate and subarticular spongiosa of the femoral heads were separately assessed by micro-computed tomography. Articular cartilage was evaluated by macroscopic and histological osteoarthritis scoring, polarized light microscopy, and immunohistochemical determination of type-I, type-II, type-X collagen contents, PTH [1-34] receptor and caspase-3 expression. Absolute and relative extents of hyaline and calcified articular cartilage layers were measured histomorphometrically. The correlation between PTH-induced changes in subchondral bone and articular cartilage was determined. PTH [1-34] enhanced volume, mineral density, and trabecular thickness within the subarticular spongiosa, and increased thickness of the calcified cartilage layer (all P<0.05). Moreover, PTH [1-34] led to cartilage surface irregularities and reduced matrix staining (both P<0.03). These early osteoarthritic changes correlated with and were ascribed to the increased thickness of the calcified cartilage layer (P=0.026) and enhanced mineral density of the subarticular spongiosa (P=0.001). Modifications of the subarticular spongiosa by PTH [1-34] cause broadening of the calcified cartilage layer, resulting in osteoarthritic cartilage degeneration. These findings identify a mechanism by which PTH-induced alterations of the normal subchondral bone microarchitecture may provoke early osteoarthritis.

Parathyroid hormone [1-34] improves articular cartilage surface architecture and integration and subchondral bone reconstitution in osteochondral defects in vivo

The 1-34 amino acid segment of the parathyroid hormone (PTH [1-34]) mediates anabolic effects in chondrocytes and osteocytes. The aim of this study was to investigate whether systemic application of PTH [1-34] improves the repair of non-osteoarthritic, focal osteochondral defects invivo. Standardized cylindrical osteochondral defects were bilaterally created in the femoral trochlea of rabbits (n=8). Daily subcutaneous injections of 10μg PTH [1-34]/kg were given to the treatment group (n=4) for 6 weeks, controls (n=4) received saline. Articular cartilage repair was evaluated by macroscopic, biochemical, histological and immunohistochemical analyses. Reconstitution of the subchondral bone was assessed by micro-computed tomography. Effects of PTH [1-34] on synovial membrane, apoptosis, and expression of the PTH receptor (PTH1R) were determined. Systemic PTH [1-34] increased PTH1R expression on both, chondrocytes and osteocytes within the repair tissue. PTH [1-34] ameliorated the macro- and microscopic aspect of the cartilaginous repair tissue. It also enhanced the thickness of the subchondral bone plate and the microarchitecture of the subarticular spongiosa within the defects. No significant correlations were established between these coexistent processes. Apoptotic levels, synovial membrane, biochemical composition of the repair tissue, and type-I/II collagen immunoreactivity remained unaffected. PTH [1-34] emerges as a promising agent in the treatment of focal osteochondral defects as its systemic administration simultaneously stimulates articular cartilage and subchondral bone repair. Importantly, both time-dependent mechanisms of repair did not correlate significantly at this early time point and need to be followed over prolonged observation periods.

Effect of Subchondral Drilling on the Microarchitecture of Subchondral Bone

Background: Marrow stimulation techniques such as subchondral drilling are clinically important treatment options for symptomatic small cartilage defects. Little is known about whether they induce deleterious changes in the subchondral bone. Hypothesis: Subchondral drilling induces substantial alterations of the microarchitecture of the subchondral bone that persist for a clinically relevant postoperative period in a preclinical large animal model. Study Design: Controlled laboratory study. Methods: Standardized full-thickness chondral defects in the medial femoral condyles of 19 sheep were treated by subchondral drilling. Six months postoperatively, the formation of cysts and intralesional osteophytes was evaluated. A standardized methodology was developed to segment the ovine subchondral unit into reproducible volumes of interest (VOIs). Indices of bone structure were determined by micro–computed tomography (micro-CT). Results: Analysis of the microarchitecture revealed the absence of zonal stratification in the ovine subarticular spongiosa, permitting an unimpeded and simultaneous analysis of the entire subchondral trabecular network. Subchondral drilling led to the formation of subchondral bone cysts (63%) and intralesional osteophytes (26%). Compared with the adjacent unaffected subchondral bone, drilling induced significant alterations in nearly all parameters for the microarchitecture of the subchondral bone plate and the subarticular spongiosa, most importantly in bone volume, bone surface/volume ratio, trabecular thickness, separation, pattern factor, and bone mineral density (BMD) (all P ≤ .01). Conclusion: The data show that the ovine subchondral bone can be reliably evaluated using micro-CT with standardized VOIs. We report that subchondral drilling deteriorates the microarchitecture both of the subchondral bone plate and subarticular spongiosa and decreases BMD. These results suggest that the entire osteochondral unit is altered after drilling for an extended postoperative period. Clinical Relevance: The subchondral bone remains fragile after subchondral drilling for longer durations than previously expected. Further evaluations of structural subchondral bone parameters of patients undergoing marrow stimulation are warranted.

Biological aspects of early osteoarthritis

Early OA primarily affects articular cartilage and involves the entire joint, including the subchondral bone, synovial membrane, menisci and periarticular structures. The aim of this review is to highlight the molecular basis and histopathological features of early OA. Selective review of literature. Risk factors for developing early OA include, but are not limited to, a genetic predisposition, mechanical factors such as axial malalignment, and aging. In early OA, the articular cartilage surface is progressively becoming discontinuous, showing fibrillation and vertical fissures that extend not deeper than into the mid-zone of the articular cartilage, reflective of OARSI grades 1.0-3.0. Early changes in the subchondral bone comprise a progressive increase in subchondral plate and subarticular spongiosa thickness. Early OA affects not only the articular cartilage and the subchondral bone but also other structures of the joint, such as the menisci, the synovial membrane, the joint capsule, ligaments, muscles and the infrapatellar fat pad. Genetic markers or marker combinations may become useful in the future to identify early OA and patients at risk. The high socioeconomic impact of OA suggests that a better insight into the mechanisms of early OA may be a key to develop more targeted reconstructive therapies at this first stage of the disease. Systematic review, Level II.

The basic science of the subchondral bone

In the past decades, considerable efforts have been made to propose experimental and clinical treatments for articular cartilage defects. Yet, the problem of cartilage defects extending deep in the underlying subchondral bone has not received adequate attention. A profound understanding of the basic anatomic aspects of this particular site, together with the pathophysiology of diseases affecting the subchondral bone is the key to develop targeted and effective therapeutic strategies to treat osteochondral defects. The subchondral bone consists of the subchondral bone plate and the subarticular spongiosa. It is separated by the cement line from the calcified zone of the articular cartilage. A variable anatomy is characteristic for the subchondral region, reflected in differences in thickness, density, and composition of the subchondral bone plate, contour of the tidemark and cement line, and the number and types of channels penetrating into the calcified cartilage. This review aims at providing insights into the anatomy, morphology, and pathology of the subchondral bone. Individual diseases affecting the subchondral bone, such as traumatic osteochondral defects, osteochondritis dissecans, osteonecrosis, and osteoarthritis are also discussed. A better knowledge of the basic science of the subchondral region, together with additional investigations in animal models and patients may translate into improved therapies for articular cartilage defects that arise from or extend into the subchondral bone.

Trabecular trajectory in the articular processes of the human fourth cervical vertebra.

The articular processes (AP) of the neural arch have been implicated in weight transmission through the cervical spine. To analyse the mechanism of weight transmission in the AP, we studied the direction of forces within it, in particular, the pattern of trabecular trajectories. Twenty-two AP from C4 vertebrae were studied in anatomical sections, and corresponding photoelastic models from selected sections were constructed and analysed. Anatomical and photoelastic findings show the subarticular spongiosa of the superior articular process (SAP) to be orthogonally arranged with vertical and oblique trabeculae in the direction of compressive forces and additional trabeculae always oriented perpendicular to the former. Vertical and oblique trabeculae are divided into rostral, middle and posterior groups. Rostral and middle trabeculae end in the anterior wall of the SAP and the transitional zone with the pedicle. Posterior trabeculae end in the subarticular spongiosa of the inferior articular process (IAP). The findings relating to trabecular trajectories in the SAP differ from previous descriptions and instead suggest that a part of the weight forces distributed within the AP transmit to the subchondral zone of the IAP. Knowledge of the trajectorial architecture of the AP may contribute to refining finite element analytical models for investigating its weight-bearing function.