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Osteoarthritis (OA) is a slowly progressive degenerative joint disorder characterized by cartilage damage, changes in periarticular bone including osteophyte formation and a sequence of subchondral changes finally leading to sclerosis, and, occasionally, inflammation of the synovial tissue. Clinical features include pain, joint stiffness, and loss of joint function. Despite numerous identified predisposing factors and the involvement of mechanics, the exact pathogenesis is still a subject of debate and research. Specifically, the very early changes are largely unknown, as they cannot easily be studied in humans because these changes appear long before the disease is diagnosed in clinical practice. The limited disease-modifying effects of many of today's treatments may be the result of the relatively late stage at which they are applied. Preferably, structure-modifying treatments should be applied early in the course of the disease. Moreover, it might well be that there are different pathways (early in the disease) that lead to an (apparently) common outcome. Today, more and more knowledge is being gained about the involvement of subchondral bone in the development of the disease. In-depth knowledge would enable specific, targeted therapies, presumably for different subtypes of the disease.

In established OA, cartilage damage is of primary concern, but total joint homeostasis relies on the biochemical and biomechanical interaction of all tissues involved, including the underlying bone. Little by little, the role of subchondral bone changes in the development of OA is becoming clearer. It is generally accepted now that the trabecular bone and the subchondral plate are different entities and can respond differently and independently in the degenerative process (1–3). In established OA, subchondral sclerosis is the indisputable result of plate thickening and an increase in trabecular volume.

The very early changes are, however, less well defined. Unfortunately, in human studies (in vivo or ex vivo), mostly established (severe) OA is studied. We lack longitudinal data on subchondral bone changes in humans from disease onset until full-blown clinical OA. Moreover, existing noninvasive (in vivo) analytic methods of determining subchondral bone changes have low sensitivity, and small changes are therefore difficult to quantify.

Most of the knowledge is now gained from animal models of OA (4–6). This has significant advantages. The use of microfocal computed tomography (micro-CT) has facilitated detailed evaluation of subchondral bone. Moreover, the use of smaller animal models such as mice enables even in vivo longitudinal evaluation by micro-CT. From this work, it has become clear that early in the disease, in addition to cartilage damage, the underlying subchondral plate is thinning, in contrast to changes found in human end-stage OA. Trabecular changes are less well clarified. In some animal models, more advanced stages of the disease can be studied, as in certain guinea pig models. In these more advanced stages, subchondral sclerosis similar to that in established human OA can be found (7). This suggests that bone remodeling is a biphasic phenomenon (i.e., an early decrease in subchondral plate thickness followed by a phase in which the subchondral bone becomes denser and stiffens). Recently, the overall decrease in bone volume was also found in early OA in humans, supporting the biphasic response theory (8). As such, these animal models are of major importance in elucidating the subchondral bone changes. Despite similarities, different models have different causes, and subchondral bone changes will behave differently. These different models may represent different forms of OA in humans. Nevertheless, translation of knowledge from animal models to humans should always be done with caution.

The subchondral plate not only provides structural support, but also acts as a portal for biochemical interaction, facilitating cross-talk between articular cartilage and bone. It was recently shown that the hydraulic conductance of osteochondral tissue and subchondral bone plate was higher (2,700-fold and 3-fold, respectively) in samples from patients with severe OA than in samples from normal healthy subjects (9). Subchondral bone plate vascularity was altered with increasing stages of OA. This indirectly showed the influence of changes in the subchondral plate and its role in homeostasis. This is further supported by the increase in plate porosity described both in OA patients and in animal models of OA (6, 10), although it is unclear if this increased porosity also leads to increased interactions between cartilage and subchondral bone.

The study by Botter et al (11) reported in this issue of Arthritis & Rheumatism examined the cartilage–subchondral bone interface using a combined approach of histology and in vivo micro-CT in a murine collagenase model of instability-induced OA. At 2, 4, 6, 10, and 14 weeks after OA induction, changes in the tibial subchondral bone plate and subchondral trabeculae were analyzed.

Two weeks after OA induction, cartilage damage was significantly increased, and mineralized osteophytes were observed; these changes were sustained throughout the experiment. Simultaneously, the subchondral plate thickness decreased 2 weeks after OA induction. However, this initial thickness decrease was temporary, since 10 weeks after OA induction, the bone plate returned to its initial thickness. Similar time-dependent dynamics were found in osteoclast surface and osteoclast number. A significant increase in osteoclast surface and a nonsignificant increase in osteoclast number were observed only during the first period after induction.

In their model, at multiple locations, the subchondral bone plate had become so thin that perforations started to appear, forming connecting tunnels between the subchondral trabecular bone/bone marrow and the articular cartilage. This was further supported by the findings of histologic analysis. The study by Botter et al shows very nicely quantitative longitudinal data on the dynamic changes in the subchondral bone plate in an experimental murine model of OA. The development of plate perforations may enhance bidirectional interactions between the bone cavity (including bone marrow cells in addition to osteoblasts and osteoclasts) and the articular cartilage in OA.

Although this is a very elegant study, there are some considerations regarding the murine collagenase-induced OA model used by these investigators. Several aspects should be taken into account when choosing a model. In general, it may be deduced that cartilage from smaller species is more cellular than that from larger species and, as such, has a higher matrix turnover rate. In addition, the thickness of cartilage varies widely from species to species. Furthermore, human cartilage is characterized by significant variations in the topographic distribution of its components, such as collagen, proteoglycans, etc., not only in cartilage from different areas of the same joint, but also between different joints and between the same joints of different individuals of the same species, irrespective of age and sex. Also, the high turnover of tissue in smaller models is a major concern. The smaller the species used, the larger the potential difference from humans, as slow development is expected to be related to slow cure, assuming cure is possible. This becomes even more complicated when characteristics of tissue aging and chondrocyte senescence are taken into account—characteristics hardly present in smaller models but presumably of major relevance to human OA. However, larger animal models have their restrictions with respect to micro-CT. Longitudinal in vivo evaluation is not yet possible.

Studies in which cartilage changes and subchondral bone changes are related both in early disease onset and over time are of indisputable value to a better understanding of the pathogenesis of OA. Several studies clearly show that the process of plate thinning underneath cartilage damage has both mechanical (2, 3) and biochemical (9) consequences. As soon as the sequence of interactions between bone and cartilage is elucidated and the mediators involved are identified, more targeted therapies can be developed. In that respect, the biphasic aspect of subchondral bone changes has to be kept in mind and may determine the effectiveness and mechanism of action of different treatment modalities.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. AUTHOR CONTRIBUTIONS
  3. REFERENCES

Drs. Mastbergen and Lafeber drafted the article, revised it critically for important intellectual content, and approved the final version to be published.

REFERENCES

  1. Top of page
  2. AUTHOR CONTRIBUTIONS
  3. REFERENCES
  • 1
    Burr DB. Anatomy and physiology of the mineralized tissues: role in the pathogenesis of osteoarthrosis. Osteoarthritis Cartilage 2004; 12 Suppl A: S2030.
  • 2
    Intema F, Hazewinkel HA, Gouwens D, Bijlsma JW, Weinans H, Lafeber FP, et al. In early OA, thinning of the subchondral plate is directly related to cartilage damage: results from a canine ACLT-meniscectomy model. Osteoarthritis Cartilage 2010; 18: 6918.
  • 3
    Intema F, Sniekers YH, Weinans H, Vianen ME, Yocum SA, Zuurmond AM, et al. Similarities and discrepancies in subchondral bone structure in two differently induced canine models of osteoarthritis. J Bone Miner Res 2010; 25: 16507.
  • 4
    Boyd SK, Muller R, Leonard T, Herzog W. Long-term periarticular bone adaptation in a feline knee injury model for post-traumatic experimental osteoarthritis. Osteoarthritis Cartilage 2005; 13: 23542.
  • 5
    Dedrick DK, Goldstein SA, Brandt KD, O'Connor BL, Goulet RW, Albrecht M. A longitudinal study of subchondral plate and trabecular bone in cruciate-deficient dogs with osteoarthritis followed up for 54 months. Arthritis Rheum 1993; 36: 14607.
  • 6
    Sniekers YH, Intema F, Lafeber FP, van Osch GJ, van Leeuwen JP, Weinans H, et al. A role for subchondral bone changes in the process of osteoarthritis; a micro-CT study of two canine models. BMC Musculoskelet Disord 2008; 9: 20.
  • 7
    Muraoka T, Hagino H, Okano T, Enokida M, Teshima R. Role of subchondral bone in osteoarthritis development: a comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis. Arthritis Rheum 2007; 56: 336674.
  • 8
    Bolbos RI, Zuo J, Banerjee S, Link TM, Ma CB, Li X, et al. Relationship between trabecular bone structure and articular cartilage morphology and relaxation times in early OA of the knee joint using parallel MRI at 3 T. Osteoarthritis Cartilage 2008; 16: 11509.
  • 9
    Hwang J, Bae WC, Shieu W, Lewis CW, Bugbee WD, Sah RL. Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis. Arthritis Rheum 2008; 58: 383142.
  • 10
    Li B, Marshall D, Roe M, Aspden RM. The electron microscope appearance of the subchondral bone plate in the human femoral head in osteoarthritis and osteoporosis. J Anat 1999; 195: 10110.
  • 11
    Botter SM, van Osch GJ, Clockaerts S, Waarsing JH, Weinans H, van Leeuwen JP. Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study. Arthritis Rheum 2011; 63: 269099.