Intrinsic Tissue Repair

As the body strives to maintain homeostasis of postnatal tissues and thus undergoes continuous tissue remodeling, many signals counteract destructive processes in tissues. Disease processes may allow destructive processes to become dominant, leading to loss of tissue homeostasis and loss of function. Enhancement of expression/secretion of signals counteracting the breakdown processes is a straightforward approach to restore homeostasis. Naturally occurring examples include production of soluble receptors or receptor antagonists (sTNF receptors, interleukin [IL]-1RA), use of inhibitors of matrix modeling enzymes such as tissue inhibitors of metalloproteinases (TIMPs), and inhibition of osteoclast formation caused by blocking the receptor activator of nuclear factor κB (NFκB) (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Some of these targets have reached the clinic; others are in early or late phase clinical trials across a range of diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA). Note, however, that in some arthritic diseases such as ankylosing spondylitis, the tissue response is abnormal, leading to joint ankylosis (for review, see Lories et al ⁸).

Because postnatal tissue repair mimics in many aspects tissue formation during development, strong arguments have been put forth for the belief that developmental pathways involved in formation of the joint and joint-associated tissues may be interesting targets for enhancing tissue repair. Typical developmental pathways critically involved in the formation of skeletal tissues and structures such as the synovial joints are contained in the transforming growth factor (TGF)-β superfamily, including bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs), the Wnt family of proteins, fibroblast growth factors (FGFs), the hedgehog (Hh) proteins, parathyroid hormone (PTH)/PTH-related protein (PTHrP), and notch signaling. It is not the intention of this chapter to discuss in detail these pathways, but rather to select a few examples of how these signaling pathways are involved in joint formation and to discuss their role in postnatal joint repair. Specific focus is placed on some of those pathways that have led to advances in early clinical development of arthritic disease.

TGF-β/BMP Signaling

Recent reviews have highlighted the relevance and critical role of members of the TGF-β superfamily (TGF-β, BMPs, GDFs) in the biology of articular cartilage, bone, joints, and joint-associated tissues, during development, in postnatal tissue homeostasis and repair, and in tissue response on injury and aging. TGF-β has been shown to be involved in the maintenance and aging of articular cartilage and in osteoarthritis.⁹ BMPs have been reported to play major roles in articular cartilage metabolism, with BMP7/OP1 being of particular interest.^10,¹¹ In addition, data indicate that modulation of TGF-β/BMP downstream receptor-Smad signaling plays an essential role in both the regulation of chondrocyte differentiation and the development and progression of osteoarthritis.¹² It is therefore not surprising that because of overwhelming evidence of the regenerative potential of this family of growth and differentiation factors in preclinical models, their therapeutic potential is being explored. In particular, several ongoing phase I studies on osteoarthritis of the knee are seeking to target OP1/BMP7 (clinicaltrials.gov). In addition, a search is ongoing, through peptide technology (peptidomimetics) or small molecule screens, to identify modulators of the TGF-β/BMP receptor/Smad signaling pathways.¹³ Because the nature of the synovial joint allows for local treatment, it is expected that some of the newly identified compounds will first be tested in local application such as joint surface repair. Indeed because this family of proteins, in particular the BMPs, plays a role in many systemic processes, BMP technology may be required to focus in the first place on local treatment, as exemplified in the use of BMP devices already in the clinic for orthopedic applications such as spine fusion and healing of nonunion.^14,¹⁵ Wider systemic morbidity upon targeting BMP pathways is as yet unclear.

FGF Signaling

Extensive investigations have identified FGFR3 signaling as a key regulator of chondrocyte and osteoblast function both during development and postnatally. In particular, absence of signaling through FGFR3 in the joints of Fgfr3^−/− mice leads to premature cartilage degeneration and early arthritis.¹⁶ These degenerative changes were accompanied by increased expression of MMP13 and type X collagen, cellular hypertrophy, and loss of proteoglycan at the articular surface. One of the key ligands of FGFR3 signaling appears to be FGF18 (for review, see Haque et al¹⁷). In the postnatal joint, FGF18 has significant anabolic effects on cartilage metabolism. The efficacy of FGF18 was tested in a rat meniscal tear model of OA.¹⁸ Intra-articular injection of FGF18 induced a dose-dependent increase in cartilage formation and a reduction in cartilage degeneration scores in the medial tibial plateau of OA rats. It is important to note that this effect was seen only in OA joints, not in normal rat joints, suggesting that this effect may be a specific response to tissue injury. It is interesting to note that at the molecular level, this joint protective effect may be due in part to its interaction with other signaling pathways such as BMP signaling by repressing noggin, a BMP antagonist.¹⁹ These findings, combined with enhanced understanding of FGF18 signaling in postnatal cartilage and bone biology, led to the development of local treatment with FGF18 and the design of early-phase clinical trials (clinicaltrials.gov) in patients with cartilage lesions and in those with OA of the knee.

Wnt Signaling

Recent findings indicate a critical role for Wnt signaling in cartilage and bone biology, with specific relevance to osteoporosis and osteoarthritis (for review, see Luyten et al ²⁰). Most available data provide circumstantial and/or direct evidence, both in vivo and in vitro, that activation of Wnt/β-catenin signaling leads to reprogramming of articular chondrocytes toward catabolism or loss of their stable phenotype, with subsequent loss of articular cartilage tissue structure and function. Frzb^−/− mice lacking this Wnt antagonist show increased activity of the Wnt signaling pathway, leading to increased bone stiffness and enhanced cartilage damage.²¹ It is important to note that upon induction of joint changes reminiscent of OA by enzymatic treatment (papain-induced osteoarthritis), by accelerated instability (collagenase-induced ligament and meniscal damage), or by inflammation (methylated bovine serum albumin [mBSA]-induced monoarthritis), Frzb^−/− mice showed greater cartilage loss than their wild-type counterparts.²² Increased cartilage damage in Frzb^−/− mice was associated with higher levels of β-catenin–dependent Wnt signaling and with higher expression levels of matrix metalloproteinase 3. It was also demonstrated that FRZB can inhibit directly matrix metalloproteinase 3, probably through the netrin domain, indicating the potential complexity of the underlying mechanisms of observed phenomena. The role of Wnt signaling as a key regulatory pathway in postnatal joint biology and joint remodeling in chronic arthritis was further highlighted by the findings of Diarra and co-workers.²³ Through inhibition of DKK1, an antagonist of the canonical Wnt signaling pathway, in a transgenic mouse model of TNF-driven inflammatory arthritis, part of the bone destructive effect was reversed. In view of the complexity of Wnt signaling and its potential downstream effects, it is important to further study the specific roles of canonical and noncanonical Wnt signaling in cartilage, bone, and the osteochondral junction, allowing Wnt-activated pathways and their components to become separate targets for therapeutic intervention. In view of this, recent findings of specific upregulation of Wnt16 in postinjury joint cartilage and in OA are of interest and open the opportunity for joint-specific Wnt targeting.²⁴