Gunnar B. J. Andersson

Recombinant human osteogenic protein–1 (RHOP-1) upregulates extracellular matrix metabolism by human annulus fibrosus and nucleus pulposus cells

Abstract Purpose of study: Recombinant human osteogenic protein–1 (rhOP-1) was recently shown to be a potent stimulator of cartilage matrix repair. It was also found to stimulate proteoglycan (PG) and collagen synthesis by rabbit nucleus pulposus (NP) and annulus fibrosus (AF) cells [1], suggesting that it may be applied intradiscally for the treatment of disc degeneration. At this time, however, it is not known if human adult NP and AF cells can be similarly stimulated by OP-1. The purpose of this study was to examine the effect of OP-1 on cell proliferation and PG synthesis by human NP and AF cells cultured in alginate gel. Methods used: Human lumbar intervertebral discs were obtained from an adult patient who underwent anterior lumbar discectomy and fusion for scoliosis. The NP and AF were separated by blunt dissection and separately pooled. Cells were enzymatically released from each tissue by digestion with 0.4% pronase for 1 hour and then with 0.025% collagenase P and 0.004% deoxyribonuclease II for 16 hours. The isolated cells were encapsulated in 1.2% low-viscosity alginate at 2 million cells /ml, as previously described [2]. After overnight culture in DMEM/F12 plus 10% FBS, the cells were cultured for another 14 days in this medium in the absence or presence of rhOP-1 (a gift from Stryker Biotech) at 20 or 200 ng/ml. The medium was changed daily. The content of DNA was measured using the Hoechst 33258 dye method and fluorometry [2]. The rate of PG synthesis was assessed by incubating the beads for the last 4 hours of culture in medium containing 35S-sulfate (20 uCi/ml) on day 14. The radiolabeled PGs were measured by a rapid filtration assay [3]. Total PG content in the beads was also assessed using the dimethylmethylene blue staining method [2] after papain digestion. of findings: Recombinant human OP-1 did not have a significant effect on cell proliferation in either cell type. The DNA content on day 14 was similar in beads cultured with or without rhOP-1. Recombinant human OP-1 significantly stimulated PG synthesis on day 14 by both AF and NP cells ( Fig. 1 Download : Download high-res image (82KB) Download : Download full-size image Fig. 1 . Effects of rhOP-1 on PG synthesis. ; NP, p Relationship between findings and existing knowledge: The results of this study show that rhOP-1 enhanced the production of PG by human NP and AF cells (Fig. 1) . Overall significance of findings: The results presented here suggest that rhOP-1 could prove most useful as a therapeutic agent in promoting synthesis and repair of matrix of both the AF and NP elements of degenerating human intervertebral discs. Disclosures: Device or drug: recombinant human osteogenic protein-1. Status: investigational. Conflict of interest: No conflicts.

Factors influencing the cost of chronic low back injuries: An analysis of data from independent medical examinations.

Cost factors were examined in 157 patients with work- related spine injuries who were referred to a second opinion program between 1985 and 1991. The independent medical examination (IME) included a history, physical examination, and review of imaging and other studies. Data on demographic variables, litigation, work, injury history, physical examination, and imaging studies were recorded. A standard measure of psychological status (Low Back Pain Symptom Check List) was filled out. The instrument uses pain language as a clinical marker of psychological disturbance linked to a range of conflictual issues such as suppressed anger, burdensome feeling of inferiority, damaged self- esteem, role confusion, abnormal mentation, fear of responsibility or intimacy, gender issues, sexual concerns, disturbing arousal, and the like. Since it relies exclusively on pain language for diagnosis, it does not identify the specific nature of the psychological conflict. Data on treatment, final resolution, and cost were obtained from computerized files of the insurance company. The total cost incurred was

The patient with spinal infection

6,551,139. This averaged to

The patient with a spine tumor

41,727 per case. More expensive cases were associated with a surgical intervention, psychological disturbance, litigation, motor weakness, and positive radiographs. These five variables accounted for 48% of the cost variance. Surgery accounted for 19.9% of the variance and contained the most expensive cases (

The patient with acute low back pain

68,310 vs.

The patient with inflammatory spine disease

31,423). Psychological disturbance was detected in 27% of the sample and accounted for 10.5% of the cost variance. Litigation was present in 72% of the cases and accounted for 9.1% of the cost variance. Motor strength and radiographs taken together accounted for 8.4% of the variance. The usefulness of this information was explored from an actuarial and medical perspective.

The patient with functional disease/malingering

The key problem in spinal infection is the failure of the medical community to appreciate that these problems continue to exist and are actually relatively common and increasing in frequency. The increase in frequency is due to several factors: (1) Our elderly population is increasing, and even without concurrent illnesses this group has a less than normal competent immune system. (2) An increasing number of patients with immune deficiencies, either of the infectious acquired type or secondary to treatment of malignant or autoimmune disease. (3) Large migrations of populations from TB endemic regions.

The patient with lower back pain, sciatica, and inability to void

Tumors of the spine are comparatively uncommon, but the consequences can be disastrous. Therefore the possibility of a tumor in a patient presenting with low back pain should be kept in mind. Tumors producing lower back pain can be either benign or malignant; they can be either primary or metastatic; they can be in the bone, in the epidural space or inside the thecal sac. Primary tumors of the spine or its contents are rare, but metastatic tumors are not uncommon in older age groups. Metastatic lesions most often involve the bone, less often the epidural space, and rarely metastatic lesions may be intrathecal. On occasion, tumors involving the pelvis can mimic one of the lumbar spine syndromes, and tumors of the lower extremity can mimic sciatica (Boland et al., 1987; Mindell, 1981; Schajowicz, 1981; Sim et al., 1977; Simone and Lawner, 1982; Weinstein and McLain, 1987).

The patient with lower back pain and leg pain with walking

The twelve symptoms and signs in Table 1 constitute the most common significant clinical syndrome in the constellation of syndromes in which “acute low back pain” is the central unifying symptom. It is rare, however, that the actual patient’s symptoms and signs have a one-to-one correspondence with this list. One or several of the twelve can be missing. However, significant deviations from this list should warn the clinician that a different and possibly more serious pathological condition may be present. Conversely, absolute correspondence with this list does not guarantee that the pathologies described below are the cause of the patient’s symptoms. The physician must be diligent in observing the patient’s changing state so as to detect changes that will require a new analysis of the patient’s status and a new approach to diagnosis and treatment.

The adult patient with spine deformity and low back pain

The syndrome described in Table 1 is caused by a group of inflammatory diseases which are thought to result from a derangement of the immune mechanism of the body. These so-called sero-negative spondylarthropathies share a variety of clinical, radiographic and genetic features (Kohler and Vaughan, 1982; Moll, 1974; Brewerton et al. 1973; Jayson, 1986). Although, both inflammatory arthritis and spondylitis are major components of each of these diseases, they are not to be thought of as variations of rheumatoid arthritis. This clinical distinction is important since complications, response to therapy and progress are quite different. Inflammatory spinal disease, extra-articular foci, particularly eye disease, and a tendency for onset in young, mainly male, adults are uniting features linking this group of diseases together. Additionally, three of the five subgroups in this category have a very high incidence of the histocompatibility antigen HLA-B27 among those afflicted with the spinal component of the disease, and an even greater proportion are HLA-B27 positive if they manifest both the eye and spinal components (Table 2). The five sub-groups to be considered are: (1) ankylosing spondylitis; (2) “reactive arthritis”; (3) Reiter’s syndrome; (4) inflammatory bowel disease; and (5) psoriasis (Table 3). In the inflammatory bowel disease and psoriasis the HLA-B27 antigen is not a factor unless there is spinal involvement and then not nearly in as great a proportion as in the other three groups (Mills et al., 1975).