The short-term therapeutic effect of recombinant human bone morphogenetic protein-2 on collagenase-induced lumbar facet joint osteoarthritis in rats

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The short-term therapeutic effect of recombinant human bone morphogenetic protein-2 on collagenase-induced lumbar facet joint osteoarthritis in rats T.-T. Yeh, M.D., S.-S. Wu, M.D., C.-H. Lee, M.D., Z.-H. Wen, Ph.D., H.-S. Lee, M.D., Ph.D., Z. Yang, M.D., M.E. Nimni, Ph.D., B. Han, Ph.D. Osteoarthritis and Cartilage Volume 15, Issue 12, Pages 1357-1366 (December 2007) DOI: 10.1016/j.joca.2007.04.019 Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Experimental protocol and representative section of collagenase-induced OA of the facet joint. (A) Experimental protocol. In the right-side facet joint, OA was induced by an intra-articular injection of 5U of collagenase type II. After 2 weeks, four groups were studied according to the different treatments. (B) Photograph of facet joint stained with Safranin O. The left-side facet joint was used as normal control. The right-side facet joint showed spontaneous healing without treatment at 3 weeks. IAP=inferior articular process of vertebra. SAP=superior articular process of vertebra. IVD=intervertebral disc. Bar=1mm. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Photographs of facet joint cartilage stained with Safranin O in the normal control group (A,B), collagenase-exposed joint (C–J), the untreated group (C,D), the saline-treated group (E,F), the rhBMP-2 10ng treated group (G,H), and the rhBMP-2 100ng treated group (I,J) at 3 and 6 weeks after treatment. In the normal control group (A,B), the articular surface was intact (black arrow). The cartilage matrix stained strongly with Safranin O. In the untreated group (C,D) and the saline-treated group (E,F), fissures extending into the middle and deep zones (long white arrow) and cartilage erosion (long black arrow) were observed. The cartilage matrix with loss of Safranin O staining was noted. Chondrocyte cloning (short white arrow) and hypocellularity of chondrocyte (short black arrow) were observed. Inter-trabecular fibrous tissue proliferation including young fibroblasts and new blood vessels, and focal new bone formation were observed (open arrow). In the rhBMP-2-treated groups (G–J), the severity of structure damage was decreased (arrow). Chondrocyte proliferation was observed. Most of the cartilage matrix was stained well with Safranin O. Focal changes in subchondral bone were observed (open arrow). Bar=500μm. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Safranin O stained sections showed adverse side effects of high dosage rhBMP-2 treatment. (A) Normal control of facet joint. (B) Three weeks after rhBMP-2 100ng injection, overgrowth of cartilage (long white arrow) and severe proliferation of synovial fibroblast (short black arrow) caused an obliteration of joint space. Chondrophyte formation was observed (long black arrow). Multifocal fragmentation of bony trabeculae surrounded by osteoclast and fibrous tissue was noted (open arrow). Bone marrow elements were replaced by loosely arranged spindle cells in a fibrous stroma. Hypertrophy of the superior articular process of vertebra was noted (double black arrows). The representative photographs in A and B were obtained from the same section. (C) Six weeks after rhBMP-2 100ng injection, newly formed osteophyte (black arrow) was observed (A–C: bar=1mm). (D) A higher magnification of the rectangular outlines in C demonstrates the process of endochondral ossification. Bar=200μm. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Histological scores for cartilage in facet joint for the normal control, the untreated group, the saline-treated group, the rhBMP-2 10ng treated group, and the rhBMP-2 100ng treated group at 3 and 6 weeks post-treatment. The values presented are the means and standard deviation for six animals. (A) Shown are values of the modified Mankin scores with comparisons between groups. (B) Shown are scores for the histologic parameters (structure, chondrocyte, and Safranin O staining) with comparisons between groups. † P<0.01, * P<0.05: significantly greater than the normal control group; # P<0.01, § P<0.05: significantly less than the untreated group; ¶ P<0.01, ‡ P<0.05: significantly less than the saline-treated group; Δ P<0.05: significantly less than the rhBMP-2 100ng treated group, by the Mann–Whitney U test. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 (A–J) Histological demonstration of synovium stained with H&E, the normal control group (A,B), collagenase-induced OA (C–J), the untreated group (C,D), the saline-treated group (E,F), the rhBMP-2 10ng treated group (G,H), and the rhBMP-2 100ng treated group (I,J) at 3 and 6 weeks after treatment. In the normal control (A,B), the synovium consists of a thin layer of synovial cells (black arrow) on top of a loose connective tissue subintimal layer (white arrow). In the collagenase-exposed joint (C–J), synovial reaction included hypertrophy or hyperplasia of synovial lining cells (long black arrow), proliferation of granulation tissue (long white arrow), and infiltration of inflammatory cells. Bar=100μm. (K) Synovium score with comparisons between groups at 3 and 6 weeks. # Significantly greater than the normal control group (P<0.01); § significantly greater than the untreated group (P<0.01); * significantly greater than the saline-treated group (P<0.01); ¶ significantly greater than the 10ng of rhBMP-2-treated group (P<0.05), by the Mann–Whitney U test. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 (A) Representative immunohistochemical stain score for collagen type II. Bar=100μm. (B) Collagen type II was analyzed based upon the staining intensity using an arbitrary score. The values presented are the means and standard deviation for six animals. ‡ Significantly reduced compared to the normal control group; § significantly reduced compared to the rhBMP-2 10ng treated group; * significantly reduced compared to the rhBMP-2 100ng treated group (all P<0.01), by the Mann–Whitney U test. Osteoarthritis and Cartilage 2007 15, 1357-1366DOI: (10.1016/j.joca.2007.04.019) Copyright © 2007 Osteoarthritis Research Society International Terms and Conditions