Regulation of immature cartilage growth by IGF-I, TGF- β 1, BMP-7, and PDGF-AB: role of metabolic balance between fixed charge and collagen network

Cartilage growth may involve alterations in the balance between the swelling tendency of proteoglycans and the restraining function of the collagen network. Growth factors, including IGF-I, TGF-β1, BMP-7, and PDGF-AB, regulate chondrocyte metabolism and, consequently, may regulate cartilage growth. Immature bovine articular cartilage explants from the superficial and middle zones were incubated for 13 days in basal medium or medium supplemented with serum, IGF-I, TGF-β1, BMP-7, or PDGF-AB. Variations in tissue size, accumulation of proteoglycan and collagen, and tensile properties were assessed. The inclusion of serum, IGF-I, or BMP-7 resulted in expansive tissue growth, stimulation of proteoglycan deposition but not of collagen, and a diminution of tensile integrity. The regulation of cartilage metabolism by TGF-β1 resulted in tissue homeostasis, with maintenance of size, composition, and function. Incubation in basal medium or with PDGF-AB resulted in small volumetric and compositional changes, but a marked decrease in tensile integrity. These results demonstrate that the phenotype of cartilage growth, and the associated balance between proteoglycan content and integrity of the collagen network, is regulated differentially by certain growth factors

Cartilage growth and remodeling: modulation of balance between proteoglycan and collagen network in vitro with β-aminopropionitrile

Objective To examine the effect of β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase, on growth and remodeling of immature articular cartilage in vitro. Design Immature bovine articular cartilage explants from the superficial and middle layers were cultured for 13 days in serum-containing medium with or without BAPN. Variations in tissue size, accumulation of proteoglycan and collagen (COL), and tensile mechanical properties were assessed. Results The inclusion of serum resulted in expansive tissue growth, stimulation of proteoglycan and COL deposition, and a diminution of tensile integrity. Supplementation of medium with BAPN accentuated this phenotype in terms of a further increase in tissue size in explants from the superficial layer and further diminution of tensile integrity, without affecting the contents of proteoglycan and COL in explants from both the superficial and middle layers. Conclusion COL crosslinking is a major factor in modulating the phenotype of cartilage growth and the associated balance between proteoglycan content and integrity of the COL network

A Cartilage Growth Mixture Model With Collagen Remodeling: Validation Protocols

A cartilage growth mixture (CGM) model is proposed to address limitations of a model used in a previous study. New stress constitutive equations for the solid matrix are derived and collagen (COL) remodeling is incorporated into the CGM model by allowing the intrinsic COL material constants to evolve during growth. An analytical validation protocol based on experimental data from a recent in vitro growth study is developed. Available data included measurements of tissue volume, biochemical composition, and tensile modulus for bovine calf articular cartilage (AC) explants harvested at three depths and incubated for 13 days in 20% fetal borine serum (FBS) and 20% FBS+ ß-aminopropionitrile. The proposed CGM model can match tissue biochemical content and volume exactly while predicting theoretical values of tensile moduli that do not significantly differ from experimental values. Also, theoretical values of a scalar COL remodeling factor are positively correlated with COL cross-link content, and mass growth functions are positively correlated with cell density. The results suggest that the CGM model may help us to guide in vitro growth protocols for AC tissue via the a priori prediction of geometric and biomechanical properties

Oral salmon calcitonin reduces Lequesne's algofunctional index scores and decreases urinary and serum levels of biomarkers of joint metabolism in knee osteoarthritis.

OBJECTIVE: To evaluate the effects of oral salmon calcitonin (sCT) on Lequesne's algofunctional index scores and on biomarkers of joint metabolism in knee osteoarthritis. METHODS: In this randomized, double-blind trial, patients received either placebo (n = 18), 0.5 mg of sCT (n = 17), or 1 mg of sCT (n = 18) daily for 84 days. Biomarkers included C-telopeptide of type II collagen (CTX-II), type II collagen neoepitope C2C, collagenases (matrix metalloproteinase 1 [MMP-1], MMP-8, and MMP-13), stromelysin (MMP-3), tissue inhibitors of metalloproteinases 1 and 2, and hyaluronan. Statistical analysis included nonparametric tests. RESULTS: A total of 41 patients completed the study (13 in the group receiving 0.5 mg of sCT and 14 in each of the other 2 other groups). Although, on day 84, patients in both the placebo group and the group receiving 1 mg of sCT exhibited a similar significant decrease in pain scores, a significant reduction in the function score was observed only in the 2 sCT groups. On day 84, there was no significant decrease in biomarker levels in the placebo group, whereas significant reductions in the levels of both MMP-3 and hyaluronan were observed in the 2 sCT groups. The group of patients receiving 1 mg of sCT exhibited significant decreases in the levels of CTX-II, C2C, and MMP-13. CONCLUSION: By improving functional disability and by reducing levels of biomarkers that are thought to be predictive of joint space narrowing (and thus cartilage loss), oral sCT at a dose of 1 mg might be a useful pharmacologic agent in human knee OA

Articular Cartilage Mechanical and Biochemical Property Relations Before and After \u3cem\u3eIn Vitro\u3c/em\u3e Growth

The aim of this study was to design in vitro growth protocols that can comprehensively quantify articular cartilage structure–function relations via measurement of mechanical and biochemical properties. Newborn bovine patellofemoral groove articular cartilage explants were tested sequentially in confined compression (CC), unconfined compression (UCC), and torsional shear before (D0, i.e. day zero) and after (D14, i.e. day 14) unstimulated in vitro growth. The contents of collagen (COL), collagen-specific pyridinoline (PYR) crosslinks, glycosaminoglycan, and DNA significantly decreased during in vitro growth; consequently, a wide range of biochemical properties existed for investigating structure–function relations when pooling the D0 and D14 groups. All D0 mechanical properties were independent of compression strain while only Poisson\u27s ratios were dependent on direction (i.e. anisotropic). Select D0 and D14 group mechanical properties were correlated with biochemical measures; including (but not limited to) results that CC/UCC moduli and UCC Poisson\u27s ratios were correlated with COL and PYR. COL network weakening during in vitro growth due to reduced COL and PYR was accompanied by reduced CC/UCC moduli and increased UCC Poisson\u27s ratios

Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis.

OBJECTIVE: To evaluate the effect of calcitonin (CT) on the histology and biochemistry of articular cartilage from unstable operated and nonoperated knee in a canine model of experimental osteoarthritis (OA). METHODS: Eighteen dogs underwent anterior cruciate ligament transection (ACLT) of the right knee and were randomly distributed into three groups of six dogs each. From day-1 after surgery until sacrifice 84 days post-ACLT, each dog received a daily nasal spray that delivered the placebo, 100 units of CT or 400 units of CT. Histologic lesions were scored. Hyaluronan (HA) and antigenic keratan sulfate (AgKS) were quantified by enzyme-linked immunosorbent assays (ELISAs), whereas aggrecan molecules extracted under nondissociative conditions were characterized by velocity gradient centrifugation. RESULTS: All canine cruciate-deficient knees developed OA. At a daily dose of 400 units, CT had no effect on the size of osteophytes but significantly reduced the severity of cartilage histologic lesions in unstable knees. CT also enhanced the HA content as well as the size distribution and relative abundance of fast-sedimenting aggrecan aggregates in cartilage from both operated and nonoperated knees. On the other hand, in the CT-treated group, the cartilage content of AgKS increased in operated joints, but not in nonoperated joints. CONCLUSIONS: Because CT delivered as a nasal spray markedly reduced the severity of most OA changes, both at the histological and biochemical level, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury, and as well as for dogs who spontaneously rupture their ACL

Treatment with calcitonin prevents the net loss of collagen, hyaluronan and proteoglycan aggregates from cartilage in the early stages of canine experimental osteoarthritis.

OBJECTIVE: To evaluate the effect of calcitonin (CT) on the histology and biochemistry of articular cartilage from unstable operated and nonoperated knee in a canine model of experimental osteoarthritis (OA). METHODS: Eighteen dogs underwent anterior cruciate ligament transection (ACLT) of the right knee and were randomly distributed into three groups of six dogs each. From day-1 after surgery until sacrifice 84 days post-ACLT, each dog received a daily nasal spray that delivered the placebo, 100 units of CT or 400 units of CT. Histologic lesions were scored. Hyaluronan (HA) and antigenic keratan sulfate (AgKS) were quantified by enzyme-linked immunosorbent assays (ELISAs), whereas aggrecan molecules extracted under nondissociative conditions were characterized by velocity gradient centrifugation. RESULTS: All canine cruciate-deficient knees developed OA. At a daily dose of 400 units, CT had no effect on the size of osteophytes but significantly reduced the severity of cartilage histologic lesions in unstable knees. CT also enhanced the HA content as well as the size distribution and relative abundance of fast-sedimenting aggrecan aggregates in cartilage from both operated and nonoperated knees. On the other hand, in the CT-treated group, the cartilage content of AgKS increased in operated joints, but not in nonoperated joints. CONCLUSIONS: Because CT delivered as a nasal spray markedly reduced the severity of most OA changes, both at the histological and biochemical level, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury, and as well as for dogs who spontaneously rupture their ACL