Endochondral Ossification in Cartilage Repair Tissue Hampers Bone Marrow Stimulating Techniques

Bone marrow-stimulating techniques are frequently applied to induce cartilage repair. Apart from insufficient chondrogenesis of the ingrowing bone marrow stem cells (BMSCs), these techniques are hampered by excessive ossification with formation of intralesional osteophytes, in which the ingrowing BMSCs tend to undergo the inherent programme of endochondral ossification. Within this programme, the chondrocyte phenotype only represents a transient state that is followed by terminal chondrocyte differentiation and replacement of the cartilaginous tissue by osseous tissue. The transcription factor Runx2 is considered the driving force for endochondral ossification, which integrates signals from growth factors that are released from the bone marrow, including bone morphogenetic proteins (BMPs), fibroblast growth factor-2 and members of the Wnt-family among others. Anti-hypertrophic factors such as PTHrP or anti-angiogenic proteins including Chondromodulin-I or Thrombospondin-1 can inhibit the endochondral ossification. In addition, antagonists of BMPand Wnt-signalling can stabilize the non-hypertrophic chondrocyte phenotype. The generation of stable cartilage tissue, however, does not only depend on extracellular factors but also on the fate of the originating cell population. Regardless of the spectrum of specific stimuli, BMSCs are prone to finally become osteocytes rather than chondrocytes. Since there is increasing evidence for epigenetic regulation including DNA methylation and histone modification for cartilage-relevant genes, future studies will have to explore the role of genomic imprinting of adult BMSCs. However, as long as tools that stabilize a chondrocyte-specific phenotype of adult BMSCs are not available in clinical routine, the transplantation of differentiated chondrocytes may remain the method of choice for cartilage repair. *Corresponding author: Gelse K, Kolja University Hospital Erlangen, Department of Orthopaedic Trauma Surgery, Krankenhausstr. 12, 91054 Erlangen, Germany, Tel: 0049-9131-8542121; Fax: 0049-9131-8533300; E-mail: [email protected] Received December 02, 2011; Accepted January 26, 2012; Published February 03, 2012 Citation: Gelse K, Beyer C, Welsch G, Blanke M (2012) Endochondral Ossification in Cartilage Repair Tissue Hampers Bone Marrow Stimulating Techniques. Rheumatology S3:002. doi:10.4172/2161-1149.S3-002 Copyright: © 2012 Gelse K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Basic Problems of Cartilage Defects Treated by Bone Marrow-Stimulating Techniques Articular cartilage has only limited capacities for spontaneous healing in case of injury or degeneration, since the adjacent chondrocytes are largely nonmotile and remain entrapped within the surrounding matrix and, in the nonvascularized tissue, mesenchymal stem cells (MSC) have limited access to cartilage lesions. Thus, the introduction of a new cell population seems necessary to generate cartilage repair tissue. Bone marrow-stimulating techniques, such as microfracturing (MFX) or abrasion of the subchondral bone plate within the defects areas, are simple, minimally-invasive and cost-effective cartilage repair approaches that are frequently applied in clinical settings [1,2]. These techniques allow stem or progenitor cells from the bone marrow to enter the cartilage lesions. Captured within a blood clot, these bone marrow-derived stem cells (BMSCs) proliferate and produce a repair tissue that may completely fill up the defect and contribute to relieve in symptoms of the patient [1-3]. However, the forming repair tissue lacks the biomechanical properties of hyaline articular cartilage and often fails in the long run, which results in deterioration of function and recurrence of clinical symptoms [2]. The inferior quality of the repair tissue results from improper cellular differentiation of the BMSCs, which is confronted with two basic problems: a. In upper zones of the repair tissue, the chondrogenic differentiation appears to be incomplete. Thus, the ingrowing progenitor cells fail to fully differentiate into chondrocytes, which leads to the formation of fibrous or fibrocartilaginous tissue characterized by inferior biomechanical stiffness (Figure 1a) [4-8]. b. In the deeper zones of the repair tissue, the ingrowing progenitor cells tend to pass through the cascade of chondrogenic differentiation beyond the status of the mature chondrocyte and undergo terminal differentiation. The resulting chondrocyte hypertrophy is typically followed by endochondral ossification (Figure 1b). The forming osseous tissue often exceeds the original level of the subchondral bone plate in terms of intralesional osteophytes (Figure 1 and 2) [810]. While incomplete chondrogenesis and the formation of fibrocartilage is a well-recognized problem, the formation of intralesional osteophytes has just recently awakened more interest. Several studies have shown that excessive bone formation occurs in up to 70% of all lesions treated by MFX [2,3,9-13]. In experimental studies on minipigs, the volume of excessive osseous tissue accounted for more than 20% in relation to the total volume of the repair tissue [8,9]. Intralesional osteophytes affect the biomechanical properties of the repair tissue by increasing the overall stiffness [4], which might interfere with the durability of the overlying thinned cartilaginous layer. Our review will discuss the mechanisms of the undesirable endochondral ossification within cartilage repair tissue. Endochondral Ossification – the Endpoint of the Chondrogenic Differentiation Cascade Ingrowing BMSCs, the cellular key players of bone marrowstimulating techniques, are multipotent progenitor cells. Upon Citation: Gelse K, Beyer C, Welsch G, Blanke M (2012) Endochondral Ossification in Cartilage Repair Tissue Hampers Bone Marrow Stimulating Techniques. Rheumatology S3:002. doi:10.4172/2161-1149.S3-002